BRPI0407827B1 - AMINOETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS AND THEIR USES - Google Patents

Abstract

"aminoetheroaryl compounds as protein kinase inhibitors". the present invention relates to aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use. preferred compounds of formula 1 have activity as protein kinase inhibitors, including as c-met inhibitors.

Description

Invention Patent Descriptive Report for AMINO-ETHYLARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS AND THEIR USES.

FIELD OF THE INVENTION [0001] The present invention generally relates to new chemical compounds and methods. More particularly, the invention provides new aminoetheroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity, and methods of synthesizing and employing such compounds.

BACKGROUND [0002] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups in protein residues tyrosine, serine and threonine. The consequences of this seemingly simple activity are tremendous; cell growth, differentiation and proliferation, that is, virtually all aspects of cell life in one way or another depend on PK activity. In addition, the abnormal PK activity has been linked to a host of disorders, ranging from relatively non-life-threatening diseases such as psoriasis to extremely virulent diseases such as gliobastoma (brain cancer).

[0003] PKs can be conveniently divided into two classes, protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs).

[0004] One of the main aspects of PTK activity is its involvement with growth factor receptors. Growth factor receptors are cell surface proteins. When bound by a growth factor ligand, growth factor receptors are converted into an active form that interacts with proteins on the inner surface of a cell membrane. This induces phosphorylation in the receptor's tyrosine residues and other

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2/470 theins and the formation within the cell of complexes with a variety of cytoplasmic signaling molecules that, in turn, carry out numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects for the extracellular microenvironment, etc. For a more complete discussion, see Schlessinger and Ullrich, Neuron 9: 303-391 (1992), which is incorporated herein by reference including any drawings, as if fully mentioned here.

[0005] Growth factor receptors with PTK activity are known as receptor tyrosine kinases (RTKs). They comprise a large family of transmembrane receptors with diverse biological activity. At the moment, at least nineteen (19) distinct subfamilies of RTKs have been identified. An example of these is the HER RTKs subfamily, which includes EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. These RTKs consist of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues in proteins.

[0006] Another subfamily of RTK consists of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor-related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two α subunits and two fully extracellular β subunits that cross the cell membrane and contain the tyrosine kinase domain.

[0007] A third subfamily of RTK is referred to as the platelet-derived growth factor receptor (PDGFR) group that includes PDGFRa, PDGFR β, CSFIR, c-kit and c-fms. These receptors consist of glycosylated extracellular domains composed of varying numbers of immunoglobin-like loops and an intracellular domain where the

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3/470 tyrosine kinase domain is disrupted by unrelated amino acid sequences.

[0008] Another group that, because of its similarity to the PDGFR subfamily, is sometimes subincluded in the latter group is the fetal liver kinase (flk) receptor family. This group is believed to be formed of kinase-1 fetal liver kinase insertion domain receptor (KDR / FLK-1), tyrosine kinase type flk-1R, flk-4 and fms (flt-1).

[0009] Another member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor receptor (FGF) subgroup. This group consists of four receptors, FGFR1-4, and seven ligands, FGF1-7. While not well defined yet, it appears that the receptors consist of a glycosylated extracellular domain containing a variable number of immunoglobin-like loops and an intracellular domain in which the tyrosine kinase sequence is disrupted by regions of unrelated amino acid sequences.

[00010] Yet another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor receptor (VEGF) subgroup. VEGF is a dimeric glycoprotein similar to PDGF but has different biological functions and target cell specificity in vivo. In particular, VEGF is currently thought to play an essential role, which is vasculogenesis and angiogenesis.

[00011] Yet another member of the tyrosine kinase growth factor receptor family is MET, often referred to as asc-Met, also known as human hepatocyte growth factor receptor (hHGFR) tyrosine kinase. c-Met is thought to play a role in primary tumor growth and metastasis. [00012] A more complete listing of the RTK subfamilies is

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4/470 described in Plowman et al., DN & P, 7 (6): 334-339 (1994), which is incorporated by reference, including any drawings, as if fully mentioned herein.

[00013] In addition to RTKs, there is also a fully intracellular PTK family called non-receptor tyrosine kinases or cellular tyrosine kinases. The latter designation, abbreviated CTK, will be used here. CTKs do not contain extracellular and transmembrane domains. At the moment, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abi, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Src subfamily so far appears to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 8: 2025-2031 (1993), which is incorporated herein by reference, including any drawings, as if fully mentioned here.

[00014] Serine / threonine kinases, STKs, like CTKs, are predominantly intracellular although there are some STK-type receptor kinases. STKs are the most common of cytosolic kinases; that is, kinases that perform their function in that part of the cytoplasm except the cytoplasmic organelles and cytoskeleton. The cytosol is a region within the cell where much of the cell's intermediate biosynthetic and metabolic activity occurs; for example, it is in the cytosol that proteins are synthesized in ribosomes. STKs include CDk2, Raf, the ZC family of kinases, the NEK family of kinases, and BUB1. [00015] RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including, significantly, cancer. Other pathogenic conditions that have been associated with PTKs include, without limitation, psoriasis, liver cirrhosis, diabetes, angiogenesis, restenosis, eye diseases, rheumatoid arthritis and other inflammatory disorders, immune disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis and a variety in

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5/470 kidney disorders.

[00016] With respect to cancer, two of the biggest hypotheses advanced to explain the excessive cell proliferation that controls tumor development refer to the functions known to be regulated by PK. That is, it has been suggested that malignant cell growth results in a disruption in the mechanisms that control cell division and / or differentiation. Protein products of various proto-oncogenes have been shown to be involved in signal transduction trails. that regulate cell growth and differentiation. These proto-oncogen protein products include the extracellular growth factors, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs) and cytosolic STKs, described above.

[00017] In view of the apparent link between cellular activities related to PK and a wide variety of human disorders, it is no surprise that a huge effort is being expended in an attempt to identify ways to modulate PK activity. Some of these have involved biomimetic methods employing large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (US Application Serial No. 4,966,849); soluble receptors and antibodies (Application No. WO 94/10202, Kendall and Thomas, Proc. Nat'l Acad .. Sci .. 90: 10705-10709 (1994), Kim, et al., Nature, 362: 841-844 (1993)); RNA ligands (Jelinek, et al., Biochemistry, 33: 10450- 56); Takano, et al., Mol. Bio. Cell, 4: 358A (1993); Kinsella, et al., Exp.Cell Res., 199: 56-62 (1992); Wright, and another, J. Cellular Phys., 152: 448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; United States Patent No. 5,330,992; Mariani, et al., Proc. Am. Assoc. Cancer Res., 35: 2268 (1994)).

[00018] In addition to the above, attempts have been made to

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6/470 identify small molecules that act as PK Inhibitors. For example, bis-monocyclic, bicyclic and heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (United States Patent No. 5,330. 992) have been described as tyrosine kinase inhibitors. Styryl compounds (United States Patent No. 5,217,999), styryl-substituted pyridyl compounds (United States Patent No. 5,302,606), quinazoline derivatives (EP Application 0 566 266A1), selenaindoles and selenides ( PCT WO 94/03427), tricyclic polyhydroxy compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) have all been described as PTK inhibitors useful in the treatment of cancer.

SUMMARY [00019] formula 1

In one embodiment, the invention provides a compound of

on what :

Y is N or CR ¹² ;

R ¹ is selected from C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , -C (O) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , C (O) -NR ⁴ R ⁵ , -NR ⁴ C (O) R ⁵ , -C (- NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ ;

R ² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2

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7/470 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR4R ⁵ , S (O) 2OR ⁴ , -NO2 , -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O ) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , and each hydrogen in R ² is optionally substituted by one or more R8 groups;

R ³ is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , -S (O) 2OR ⁴ , -NO2, NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , each hydrogen in R ³ is optionally substituted by one or more R ⁸ groups, and R 3 groups on adjacent atoms can combine to form a group of C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same nitrogen atom can, together with the nitrogen to which they are attached, be combined to form a 3- to 12-membered heteroalicyclic or heteroaryl group of 5 to 12 members containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same carbon atom can be combined to form a group of C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic or 5 to 4 heteroaryl 12 members; and each hydrogen in R ⁴ , R ⁵ , R ⁶ and R ⁷ is optionally substituted by one or more groups of R 8;

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8/470 each R ⁸ is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, - CN, -O-C1-12 alkyl, -O- (CH ₂ ) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic) or - O- (CH2) n (5- to 12-membered heteroaryl); and each hydrogen in R ⁸ is optionally substituted by one or more groups of R ¹¹ ;

A ¹ is - (CR9R ¹⁰ ) nA ² except that:

(i) when Y is N and R ¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A ¹ is - (CR9R ¹⁰ ) nA ^{2 and} n is not zero; and (ii) when Y is N and R ² is H and A ¹ is m-chlorobenzyl, R ¹ is not unsubstituted piperazine;

each R9 and R ¹⁰ is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ ; R ⁹ and R ¹⁰ can combine to form a C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, C6-12 aryl or 5 to 12 membered heteroaryl ring; and each hydrogen in R ⁹ and R ¹⁰ is optionally substituted by one or more groups of R ³ ;

A ² is C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic, and A ² is optionally substituted by one or more groups of R ³ ;

each R ¹¹ is independently halogen, C1-12 alkyl, C112 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 heteroalicyclic

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9/470 members), -O- (CH2) n (5-12 membered heteroaryl) or -CN, and each hydrogen in R ¹¹ is optionally substituted by one or more selected groups of halogen, -OH, -CN, - C1-12 alkyl that can be partially or fully halogenated, -O-C1-12 alkyl that can be partially or fully halogenated, -CO, -SO and -SO2;

R ¹² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C212 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , and each hydrogen in R ¹² is optionally replaced by one or more groups of R ³ ;

R ¹ and R ² or R ¹ and R ¹² can be combined together to form a C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

m is 0, 1 or 2;

n is 0, 1,2, 3 or 4; and p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00020] In a particular aspect of this embodiment, Y is N. In a preferred aspect, R1 is not piperazine. In another preferred aspect, R ¹ is not heteroalicyclic.

[00021] In another particular aspect of this modality, Y is CR ¹² .

[00022] In particular aspects of this modality, and in combination with any other particular aspects of this modality, the compound has the formula 1 ^a

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10/470

wherein A ² is C6-12 aryl or 5- to 12-membered heteroaryl optionally substituted by one or more groups of R ³ .

[00023] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ¹ is selected from C6-12 aryl and 5- to 12-membered heteroaryl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00024] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is selected from C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , -C (O) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , -C (O) NR ⁴ R ⁵ , NR ⁴ C (O) R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ^3. [00025] In particular aspects of this modality, and in combination with any other particular aspects of this modality, A ² is replaced by at least one halogen atom.

[00026] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ² is hydrogen, R9 and R ¹⁰ are independently C1-4 alkyl, and A ² is phenyl substituted by at least one halogen atom.

[00027] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of

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11/470 furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazine, pyridine, pyrane, pyrane, pyrane, pyrane, pyrane, pyrane, pyrane, pyrane, pyrane, pyrane , dithian, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tritian or phenyl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00028] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole ; each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ . In a more particular aspect, R ¹ is not heteroalicyclic.

[00029] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a fused ring heteroaryl group, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00030] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of SO2NR4R5.

[00031] In another embodiment, the invention provides a compound of formula 2

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12/470

nh ₂ [00032] in which:

[00033] R ¹ is selected from C6-12 aryl, 5 to 12 membered heteroaryl, C312 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , - C (O) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , C (O) -NR ⁴ R ⁵ , -NR ⁴ C (O) R ⁵ , -C (-NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ ;

[00034] R ² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C212 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S ( O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , and each hydrogen in R ² is optionally substituted by one or more groups R ⁸ ;

[00035] R ³ is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl,

C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , -S (O) 2OR ⁴ , -NO2, NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , each hydrogen in R ³ is optionally substituted by one or more R ⁸ groups, and R 3 groups on adjacent atoms can combine to form a group of C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or group

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13/470 heteroalicyclic with 3 to 12 members;

[00036] each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to heteroalicyclic 12 members, heteroaryl of 5 to 12 members; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same nitrogen atom can, together with the nitrogen to which they are attached, be combined to form a 3- to 12-membered heteroalicyclic or heteroaryl group of 5 to 12 members containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same carbon atom can be combined to form a group of C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic or 5 to 4 heteroaryl 12 members; and each hydrogen in R ⁴ , R ⁵ , R ⁶ and R ⁷ is optionally substituted by one or more groups of R 8;

[00037] each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -CN , -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic) or -O- (CH2) n (5 to 12 membered heteroaryl); and each hydrogen in R ⁸ is optionally substituted by one or more groups of R ¹¹ ;

[00038] A ¹ is - (CR9R ¹⁰ ) nA ² ;

[00039] each R ⁹ and R ¹⁰ is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ ; R ⁹ and R ¹⁰ can combine to form a C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, C6-12 aryl or 5 to 12 mem heteroaryl ring

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14/470 bros; and each hydrogen in R ⁹ and R ¹⁰ is optionally substituted by one or more groups of R3;

[00040] A ² is C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic, and A ² is optionally substituted by one or more groups of R ³ ;

[00041] each R ¹¹ is independently halogen, C1-12 alkyl, C112 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic), -O- (CH2) n (5 to heteroaryl 12 members) or -CN, and each hydrogen in R ¹¹ is optionally substituted by one or more selected groups of halogen, -OH, -CN, -C1-12 alkyl which can be partially or fully halogenated, -O-C1-12 alkyl that can be partially or fully halogenated, -CO, -SO and -SO2;

[00042] R ¹² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C212 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S ( O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , and each hydrogen in R ¹² is optionally substituted by one or more groups of R ³ ;

[00043] R ¹ and R ² or R1 and R ¹² can be combined together to form a C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

[00044] m is 0, 1 or 2;

[00045] n is 0, 1,2, 3 or 4; and [00046] p is 1 or 2;

[00047] or a pharmaceutically acceptable salt, solvate or hydrate thereof.

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15/470 [00048] In a particular aspect of this modality, the compound has the formula 2a

nh ₂ in which A ² is C1-12 aryl or 5- to 12-membered heteroaryl optionally substituted by one or more groups of R ³ .

[00049] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ¹ is selected from C6-12 aryl and heteroaryl of 5 to 12 members, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00050] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is selected from C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , C (O) R ⁴ , -C (O) OR ⁴ , -CN, NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , -C (O) NR ⁴ R ⁵ , NR4C (O) R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00051] In particular aspects of this modality, and in combination with any other particular aspects of this modality, A ² is replaced by at least one halogen atom.

[00052] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ² is hydrogen, R ⁹ and R ¹⁰ are independently C1-4 alkyl, and A ² is phenyl substituted by at least one halogen atom .

[00053] In particular aspects of this modality, and in combination

Petition 870190089642, of 10/09/2019, p. 20/482

16/470 nation with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole , pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00054] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a fused ring heteroaryl group, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00055] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of SO2NR4R ⁵ .

[00056] In another embodiment, the invention provides a compound of formula 3

R ¹

NH ₂ in which:

R ¹ is selected from C6-12 aryl, 5 to 12 membered heteroaryl, C312 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , -C (O ) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , C (O) -NR ⁴ R ⁵ , -NR ⁴ C (O) R ⁵ , -C (-NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl,

Petition 870190089642, of 10/09/2019, p. 21/482

17/470 and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R3;

R ² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C212 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR4R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C ( = NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , and each hydrogen in R ² is optionally substituted by one or more R ⁸ groups;

R ³ is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , -S (O) 2OR ⁴ , -NO2, NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , each hydrogen in R ³ is optionally substituted by one or more R ⁸ groups, and R 3 groups on adjacent atoms can combine to form a group of C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same nitrogen atom can, together with the nitrogen to which they are attached, be combined to form a 3- to 12-membered heteroalicyclic or heteroaryl group of 5 to 12 members containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same carbon atom can be combined to form a group of C3-12 cycloalkyl, C6-12 aryl, he

Petition 870190089642, of 10/09/2019, p. 22/482

18/470 teroalicyclic from 3 to 12 members or heteroaryl from 5 to 12 members; and each hydrogen in R ⁴ , R ⁵ , R 6 and R ⁷ is optionally substituted by one or more groups of R ⁸ ;

each R ⁸ is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -CN, - O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3- to 12-membered heteroalicyclic) or -O- (CH2 ) n (5 to 12 membered heteroaryl); and each hydrogen in R ⁸ is optionally substituted by one or more groups of R ¹¹ ;

A ¹ is - (CR9R ¹⁰ ) nA ² except that:

(i) when Y is N and R ¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A ¹ is - (CR9R ¹⁰ ) nA ^{2 and} n is not zero; and (ii) when R ² is H and A ¹ is m-chlorobenzyl, R ¹ is not unsubstituted piperazine;

each R9 and R ¹⁰ is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ ; R ⁹ and R ¹⁰ can combine to form a C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, C6-12 aryl or 5 to 12 membered heteroaryl ring; and each hydrogen in R9 and R ¹⁰ is optionally substituted by one or more groups of R ³ ;

A ² is C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic, and A ² is optionally substituted by one or more groups of R ³ ;

each R ¹¹ is independently halogen, C1-12 alkyl, C1

Petition 870190089642, of 10/09/2019, p. 23/482

19/470 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O - (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic), -O- (CH2) n (5 to 12 membered heteroaryl) or -CN, and each hydrogen in R ¹¹ is optionally substituted by one or more selected halogen groups, -OH, -CN, -C1-12 alkyl which can be partially or fully halogenated, -O-C1-12 alkyl which can be partially or fully halogenated, -CO, - SO and -SO2;

R ¹ and R ² can be combined together to form a C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

m is 0, 1 or 2;

n is 0, 1,2, 3 or 4; and p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00057] In a particular aspect of this modality, the compound has the formula 3a

R ¹

NH ₂ in which A ² is C6-12 aryl or 5- to 12-membered heteroaryl optionally substituted by one or more groups of R ³ .

[00058] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ¹ is selected from C6-12 aryl and 5- to 12-membered heteroaryl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

Petition 870190089642, of 10/09/2019, p. 24/482

20/470 [00059] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R1 is selected from C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR6R ⁷ ) nR ⁴ , C (O) R ⁴ , -C (O) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , -C (O) NR ⁴ R ⁵ , NR ⁴ C (O) R ⁵ , -C (= NR6) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00060] In particular aspects of this modality, and in combination with any other particular aspects of this modality, A ² is replaced by at least one halogen atom.

[00061] In particular aspects of this modality, and in combination with any other particular aspects of this modality, R ² is hydrogen, R ⁹ and R ¹⁰ are independently C1-4 alkyl, and A ² is phenyl substituted by at least one halogen atom .

[00062] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of furan, thiopene, pyrrole, pyrroline, pyrrolidines, dioxolane, oxazole, thiazole ; , and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00063] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole , imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine

Petition 870190089642, of 10/09/2019, p. 25/482

21/470 na, dioxane, morpholine, dithiano, thiomorpholine, pyridazine, pyrimidine, pyrazine, triazine, tritiano or phenyl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ . In even more particular aspects, R ¹ is not heteroalicyclic.

[00064] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of fused ring heteroaryl, and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ .

[00065] In particular aspects of this modality, and in combination with any other particular aspects of this modality not inconsistent with the following definition of R ¹ , R ¹ is a group of SO2NR4R5.

[00066] In another embodiment, the invention provides a compound of formula 4

R ¹

nh ₂ where:

R ¹ is selected from Ce-12 aryl, 5 to 12 membered heteroaryl, C312 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , -C (O ) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , C (O) -NR ⁴ R ⁵ , -NR ⁴ C (O) R ⁵ , -C (-NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R ³ ;

R ² is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C212 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 heteroalicyclic

Petition 870190089642, of 10/09/2019, p. 26/482

22/470 members, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR6R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR6R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C ( O) NR ⁴ R ⁵ , and each hydrogen in R ² is optionally substituted by one or more R8 groups;

R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR4R ⁵ , -S (O) 2OR ⁴ , -NO2, NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , each hydrogen in R ³ is optionally substituted by one or more R ⁸ groups, and R 3 groups on adjacent atoms can combine to form a group of C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic group;

each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same nitrogen atom can, together with the nitrogen to which they are attached, be combined to form a 3- to 12-membered heteroalicyclic or heteroaryl group of 5 to 12 members containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same carbon atom can be combined to form a group of C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic or 5 to 4 heteroaryl 12 members; and each hydrogen in R ⁴ , R ⁵ , R ⁶ and R ⁷ is optionally substituted by one or more groups of R 8;

each R8 is independently halogen, C1-12 alkyl, C2-12

Petition 870190089642, of 10/09/2019, p. 27/482

23/470 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O- (CH2 ) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic) or -O- (CH2) n (5 to 12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more groups of R ¹¹ ;

each R9 and R ¹⁰ is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ ; R ⁹ and R ¹⁰ can combine to form a C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, C6-12 aryl or 5 to 12 membered heteroaryl ring; and each hydrogen in R9 and R ¹⁰ is optionally substituted by one or more groups of R ³ ;

A ² is C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic, and A ² is optionally substituted by one or more groups of R ³ ;

each R ¹¹ is independently halogen, C1-12 alkyl, C112 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -O-C1-12 alkyl, -O- (CH2) nCs-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic), -O- (CH2) n (5 to 12 membered heteroaryl) or -CN, and each hydrogen in R ¹¹ is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which can be partially or fully halogenated, -O-C1-12 alkyl which can be partially or totally halogenated, -CO, -SO and -SO2;

m is 0, 1 or 2;

n is 0, 1,2, 3 or 4; and

Petition 870190089642, of 10/09/2019, p. 28/482

24/470 p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00067] In a particular aspect of this modality, A ² is C6-12 aryl or 5- to 12-membered heteroaryl, optionally substituted by one or more groups of R ³ .

[00068] In other particular aspects of this modality, substituents and groups of substituents include those defined in particular aspects of the previous modalities.

[00069] In another embodiment, the invention provides a compound of formula 5

R ¹

MH in which

R ¹ is selected from Ce-12 aryl, 5 to 12 membered heteroaryl, C312 cycloalkyl, 3 to 12 membered heteroalicyclic, -O (CR ⁶ R ⁷ ) nR ⁴ , -C (O) R ⁴ , -C (O ) OR ⁴ , -CN, -NO2, -S (O) mR ⁴ , -SO2NR4R ⁵ , C (O) -NR ⁴ R ⁵ , -NR ⁴ C (O) R ⁵ , -C (-NR ⁶ ) NR ⁴ R ⁵ , C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R3;

R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR4R ⁵ , -S (O) 2OR ⁴ , -NO2, NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , -C (= NR ⁶ ) NR ⁴ R ⁵ , NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ , each hydrogen in R ³

Petition 870190089642, of 10/09/2019, p. 29/482

25/470 is optionally substituted by one or more R ⁸ groups, and R3 groups on adjacent atoms can combine to form a group of C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 heteroalicyclic group members;

each R ⁴ , R ⁵ , R ⁶ and R ⁷ is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same nitrogen atom can, together with the nitrogen to which they are attached, be combined to form a 3- to 12-membered heteroalicyclic or heteroaryl group of 5 to 12 members containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R ⁴ , R ⁵ , R ⁶ and R ⁷ attached to the same carbon atom can be combined to form a group of C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic or 5 to 4 heteroaryl 12 members; and each hydrogen in R ⁴ , R ⁵ , R ⁶ and R ⁷ is optionally substituted by one or more groups of R ⁸ ;

each R ⁸ is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -CN, - O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3- to 12-membered heteroalicyclic) or -O- (CH2 ) n (5 to 12 membered heteroaryl); and each hydrogen in R ⁸ is optionally substituted by one or more groups of R ¹¹ ;

each R9 and R ¹⁰ are independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -S (O) mR ⁴ , -SO2NR ⁴ R ⁵ , S (O) 2OR ⁴ , -NO2, -NR ⁴ R ⁵ , - (CR ⁶ R ⁷ ) nOR ⁴ , -CN, -C (O) R ⁴ , -OC (O) R ⁴ , O (CR ⁶ R ⁷ ) nR ⁴ , -NR ⁴ C (O) R ⁵ , - (CR ⁶ R ⁷ ) nC (O) OR ⁴ , - (CR ⁶ R ⁷ ) nNCR ⁴ R ⁵ , C (= NR ⁶ ) NR ⁴ R ⁵ , -NR ⁴ C (O) NR ⁵ R ⁶ , -NR ⁴ S (O) pR ⁵ or -C (O) NR ⁴ R ⁵ ; R ⁹ e

Petition 870190089642, of 10/09/2019, p. 30/482

26/470

R ¹⁰ can combine to form a C3-12 cycloalkyl, 3 to 12 membered heteroalicyclic, C6-12 aryl or 5 to 12 membered heteroaryl ring; and each hydrogen in R9 and R ¹⁰ is optionally substituted by one or more groups of R ³ ;

A ² is C6-12 aryl, 5 to 12 membered heteroaryl, C3-12 cycloalkyl or 3 to 12 membered heteroalicyclic, and A ² is optionally substituted by one or more groups of R ³ ; except that when R ² , R ⁹ and R ¹⁰ are all He A ² is m-chlorophenyl, R ¹ is not unsubstituted piperazine.

each R ¹¹ is independently halogen, C1-12 alkyl, C112 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3 to 12 membered heteroalicyclic, 5 to 12 membered heteroaryl, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3 to 12 membered heteroalicyclic), -O- (CH2) n (5 to 12 membered heteroaryl) or -CN, and each hydrogen in R ¹¹ is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which can be partially or fully halogenated, -O-C1-12 alkyl which can be partially or totally halogenated, -CO, -SO and -SO2;

m is 0, 1 or 2;

n is 0, 1,2, 3 or 4; and p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00070] In a particular aspect of this modality, A ² is C6-12 aryl or 5- to 12-membered heteroaryl optionally substituted by one or more groups of R ³ .

[00071] In other particular aspects of this modality, substituents and groups of substituents include those defined in particular aspects of the previous modalities.

[00072] In another embodiment, the invention provides a compound sePetição 870190089642, of 10/09/2019, p. 31/482

27/470 taught from the group consisting of: 4- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -phenol; 3- (2,6-dichloro-benzyloxy) -5- [4- (2-morpholin-4yl-ethoxy) -phenyl] -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (1 H-indole-

4-yl) -pyridin-2-ylamine; 3- [2-chloro-6- (1 H-indol-4-yl) -benzyloxy] -5- (1 H-indol-4-yl) -pyridin-2-ylamine; 2- [6-amino-5 (2,6-dichloro-benzyloxy) -pyridin-3-yl] pyrrole-1-carboxylic acid tert-butyl ester; 3- (2,6-dichlorobenzyloxy) -5- (1 H-pyrrol-2-yl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5 (4-fluoro-phenyl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5-phenyl-pyridin-2-amine; 3- (2,6-dichloro-benzyloxy) -5- (2-fluoro-phenyl) -pyridin-2-ylamine; 3 (2,6-dichloro-benzyloxy) -5- (3-fluoro-phenyl) -pyridin-2-ylamine; 5- (4-aminophenyl) -3- (2,6-dichloro-benzyloxy) -pyridin-2-ylamine; M- {4- [6-amino-5- (2,6dichloro-benzyloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide; N- {4- [6-amino-

5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} -acetamide; 3- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenol; 3- (2,6-dichloro-benzyloxy) -5- (4-methoxy-phenyl) -pyridin-2-ylamine; 5- (3-amino-phenyl) -3- (2,6-dichloro-benzyloxy) pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3-trifluoromethoxy-phenyl) pyridin-2-ylamine; 2- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenol;

3- (2,6-dichloro-benzyloxy) -5- (2-phenoxy-phenyl) -pyridin-2-ylamine; 3- (2,6dichloro-benzyloxy) -5- (3,4-difluoro-phenyl) -pyridin-2-ylamine; 3- (2,6-dichlorobenzyloxy) -5- (3-isopropyl-phenyl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine; 3- (2,6-dichlorobenzyloxy) -5- (2-methoxy-phenyl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -

5- (4-trifluoromethyl-phenyl) -pyridin-2-ylamine; N- {2- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide; {4- [6-amino-5- (2,6dichloro-benzyloxy) pyridin-3-yl] -phenyl} -methanol; 5-benzo [1,3] dioxol-5-yl-3 (2,6-dichloro-benzyloxy) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (2-trifluoromethoxy-phenyl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (4-methyl-thiophen-2-yl) -pyridin-2-ylamine; 5- (2-benzyloxy-phenyl) -3- (2,6-dichlorobenzyloxy) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3-methoxy-phenyl)

Petition 870190089642, of 10/09/2019, p. 32/482

28/470 pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (1 H-indol-2-yl) pyridin-2amine; 5- (4-benzyloxy -3-fluoro-phenyl) -3- (2,6-dichloro-benzyloxy) -pyridin-2-amine; 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid;

4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -N- (2-diethylamino-ethyl) -benzamide; 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -N- (3dethylamino-propyl) -benzamide; {4- [6-amino-5 (2,6-dichloro-benzyloxy) pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; {4- [6-amino-5- (2,6dichloro-benzyloxy) -pyridin-3-yl] -phenyl) - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-

1-yl] -methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} [(2S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone ; {4- [6-amino-5- (2,6dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [4- (2-hydroxy-ethyl) -piperidin-1-yl] -methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-dimethylamino-pyrrolidin-1-yl] methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3R) -

3-dimethylamino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-cyclopropylaminomethyl-piperidin-1-yl] methanone; 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -N- (2-hydroxy

-3-pyrrolidin-1-yl-propyl) -benzamide; {4- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2- (3-fluoro-piperidin-1-ylmethyl) -pyrrolidin-

1-yl] -methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} (4-cyclopropyl-piperazin-1-yl) -methanone; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - {(2R) -2 - [(cyclopropylmethyl-amino) -methyl] pyrrolidin-1- il} -methanone; 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3yl] -N-cyclopropylmethyl-N- (2R) -pyrrolidin-2-ylmethyl-benzamide; 4- [6-amino-

5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -N- (2-hydroxy -3-pyrrolidin-1-yl-propyl) N-methyl-benzamide; {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] phenyl} - {(25) -2 - [(3R) -3-hydroxy -pyrrolidin-1-ylmethyl ] -pyrrolidin-1-yl} -methanone; 3- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid; {3- [6 amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-

Petition 870190089642, of 10/09/2019, p. 33/482

29/470 ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -phenoxy} -acetic acid; 2- {4- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -phenoxy} -1 - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] ethanone; 2- {4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 [(2S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1- il] -ethanone; 3- (2,6-dichlorobenzyloxy) -5- (1 H-indol-5-yl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5 [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1 H-indol-5-yl] -pyridin- 2-ylamine;

3- (2,6dichloro-benzyloxy) -5- [3- (1-methyl-piperidin-4-yl) -1 H-indol-5-yl] -pyridin-

2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3-morpholin-4-ylmethyl-1 H-indol-5-yl) pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3-piperidin-1-ylmethyl-1 Hindol-5-yl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3-pyrrolidin-1ylmethyl-1 H-indol-5-yl) -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5- (3dethylaminomethyl-1 H-indol-5-yl) -pyridin-2-ylamine; acid (1- {5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indol-3-methylmethyl} - (3R) -pyrrolidin -3-yl) -carbamic; 3- (2,6-dichloro-benzyloxy) -5- [3- (2,6-dimethyl-morpholin-4-ylmethyl) -1 H-indol-5-yl] -pyridin-2-ylamine; N- (9- {5 [6-amino-S- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indol-3-ylmethyl} - (3R) pyrrolidin-3-yl) -acetamide; 1- (4- {5- [6-amino-5- (2,6-dichloro-benzyloxy) pyridin-3-yl] -1 H-indol-3-ylmethyl} -piperazin-1-yl) -ethanone; 3- (2-chloro-3,6difluoro-benzyloxy) -5- (1 H-indol-5-yl) -pyridin-2-ylamine; 1- (4- {5- [6-amino-5 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -1 H-indol-3-ylmethyl} -piperazin-

1-yl) -ethanone; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- [3- (2,6-dimethyl-morpholin-

4-ylmethyl) -1 H-indol-5-yl] -pyridin-2-ylamine; N- (1- {5- [6-amino-5- (2-chloro-

3,6-difluoro-benzyloxy) -pyridin-3-yl] -1 H-indol-3-ylmethyl} - (3S) -pyrrolidin-3-yl) acetamide; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-piperidin-1-ylmethyl-1 Hindol-5-yl) -pyridin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-morpholin-4-ylmethyl-1 H-indol-5-yl) -pyridin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-pyrrolidin-1-ylmethyl-1 H-indol-5-yl) -pyridin-2-ylamine; 5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 Hindol-2-carboxylic acid ethyl ester; 5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3 acidPetition 870190089642, of 10/09/2019, p. 34/482

30/470 yl] -1 H-indole-2-carboxylic; {5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-

3-yl] -1 H-indol-2-yl} - (4-methyl-piperazin-1-yl) -methanone; {5- [6-amino-5 (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indol-2-yl} - [(3R) -3-dimethylaminopyrrolidin-1-yl] - methanone; {5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3yl] -1 H-indol-2-yl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-yl-methanone; 5- [6-amino-5- (2,6-dichloro-benzyloxy) pyridin-3-yl] -1 H-indole-2-carboxylic acid (2pyrrolidin-1-yl-ethyl) -amide; Acid (2-morpholin-4-yl-ethyl) -amide

5- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indole-2-carboxylic; (1-5- [6-amino-5- (2,6-dichloro-benzyloxy) pyridin-3-yl] -1 H-indole-2-carbonyl} - (3S) - tert-butyl ester pyrrolidin-3-yl) -carbamic; {5- [6 amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indol-2-yl} - [(3S) -3-aminopyrrolidin-1-yl] -methanone ; 5- [6-Amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indole- (2-hydroxy -3-pyrrolidin-1-yl-propyl) -amide 2carboxylic; 4- (6-amino-5-benzyloxy-pyridin-3-yl) -phenol; 3-benzyloxy-5-phenyl-pyridin-2-ylamine; 3- (3-methoxy-benzyloxy) -5-phenyl-pyridin-2-ylamine;

3- (2-chloro-4-fluoro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (2-chloro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (2,5-dichloro-benzyloxy) -5-phenylpyridin-2-ylamine; 3- (2-chloro-5-trifluoromethyl-benzyloxy) -5-phenyl-pyridin-2ylamine; 3- (2,4-dichloro-5-fluoro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (2-chloro-3-trifluoromethyl-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (2-chloro-3,6difluoro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (3,4-dichloro-benzyloxy) -5phenyl-pyridin-2-ylamine; 2- (2-amino-5-phenyl-pyridin-3-yloxymethyl) -benzonitrile; 3- (2-chloro-6-fluor-3-methyl-benzyloxy) -5-phenyl-pyridin-2-ylamine; 5-phenyl-3 (2,3,6-trifluor-benzyloxy) -pyridin-2-ylamine; 3- (2,6-difluoro-benzyloxy) -5phenyl-pyridin-2-ylamine; 3- (2,6-difluoro-3-methyl-benzyloxy) -5-phenyl-pyridin-2ylamine; 3- (3-chloro-2,6-difluoro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (2-chloro-6-fluoro-benzyloxy) -5-phenyl-pyridin-2-ylamine; 3- (3-fluoro-4-methoxy benzyloxy) -5-phenyl-pyridin-2-ylamine; N- [3- (2-amino-5-phenyl-pyridin-3yloxymethyl) -phenyl] -methanesulfonamide; 5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] 3- (3-nitro-benzyloxy) -pyridin-2-ylamine; 5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -3Petition 870190089642, of 9/10/2019, p. 35/482

31/470 (naphthalen-1-ylmethoxy) -pyridin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -

5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 2- {2-amino-5- [4- (2morpholin-4-yl-ethoxy) -phenyl] -pyridin-3-yloxy} -N- (4-isopropyl-phenyl) -2-phenylacetamide; 3- (5-chloro-benzo [b] thiophen-3-ylmethoxy) -5- [4- (2-morpholin-4-yletoxy) -phenyl] -pyridin-2-ylamine; {4- [6-amino-5- (4-fluor-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] methanone; {4- [6-amino-5- (2-fluor-6-trifluoromethyl-benzyloxy) -pyridin-3-yl] phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5 (5-fluor-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl] -methanone ; (4- {6-amino-5- [1- (2-trifluoromethyl-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1- il] methanone; {4- [6-amino-5- (2-bromo-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (3-fluor-2trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -phenyl3 - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone; 4 [6-amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenol; 3- (2,6-diflurobenzyloxy) -5- (1 H-indol-4-yl) -pyridin-2-ylamine; 3- (2,6-difluoro-benzyloxy) -5 [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 4- [6-amino-5- (2,6-fluoro-benzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] methanone; {4- [6-amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -

2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4 [6-amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic acid ethyl ester; {4 [6-amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic acid; 2- {4- [6 amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 - [(2R) -2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl] - ethanone; 2- {4- [6-amino-5- (2,6-difluoro-benzyloxy) pyridin-3-yl] -henoxy} -1 - [(2S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1- il] -ethanone;

4- [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -phenol; 4- [6-amino-5 (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] -phenol; 4- [6-amino-5- (2,4-dichloro-

Petition 870190089642, of 10/09/2019, p. 36/482

32/470 benzyloxy) -pyridin-3-yl] -phenol; 2- [2-amino-5- (4-hydroxy-phenyl) -pyridin-3yloxymethyl] -benzonitrile; 4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3yl] -phenol; 4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -phenol; 4- [6-amino-

5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -phenol; N- {4- [6-amino-5- (2-cyano-benzyloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide; 2- [2-amino-5- (4-methanesulfonylamino-phenyl) -pyridin-3-yloxymethyl] -benzamide; 2- [2 amino-5- (4-methanesulfonylamino-phenyl) -pyridin-3-yloxymethyl] -benzoic acid; N- (4- {6-amino-5- [2- (4-methyl-piperazine-1-carbonyl) -benzyloxy] -pyridin-3yl} -phenyl) -methanesulfonamide; 2- [2-amino-5- (4-methanesulfonylaminophenyl) -pyridin-3-yloxymethyl] -N- (2-hydroxy-ethyl) -benzamide; 2- [2-arhino-5- (4-methanesulfonylamino-phenyl) -pyridin-3-yloxymethyl] -N-isobutyl-benzamide; 4- [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -benzoic acid; {4 [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin1 -ylmethyl-pyrrolidin-1-yl] -methanone ; {4- [6-amino-5- (2-chloro-6-fluorobenzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] methanone ; {4- [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -phenyl} [(3S) -3-dimethylamino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-amino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-6-fluor-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methylpiperazin-1-yl) -methanone; 1- (4- {4- [6-amino-5- (2-chloro-6-fluor-benzyloxy) pyridin-3-yl] -benzoyl} -piperazin-1-yl) -ethanone; 4- [6-amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) -benzamide; 4- [6 amino-5- (2-chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) benzamide; 4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-

3-yl] -phenyl} - [(2S) -2-pyroolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6- amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-dimethylaminopyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] phenyl} - [(3S) -3-amino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloroPetition 870190089642, from 10/09/2019, pg. 37/482

33/470 benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; {4 [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; 1- (4- {4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl-benzoyl} piperazin-1-yl) -ethanone; 4- [6-amino-5- (2-chloro-benzyloxy) -pyridin-3-yl] -N (2-morpholin-4-yl-ethyl) -benzamide; 4- [6-amino-5- (2-chloro-benzyloxy) -pyridin3-yl] -N- (3-morpholin-4-yl-propyl) -benzamide; 4- [6-amino-5- (2-cyanobenzyloxy) -pyridin-3-yl] -benzoic acid; 2- {2-amino-5- [4 - ((2R) -2-pyrrolidin-1ylmethyl-pyrrolidine-1-carbonyl) -phenyl] -pyridin-3-yloxymethyl} -benzonitrile; 2- {2 amino-5- [4 - ((2S) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -phenyl] pyridin-3-yloxymethyl} -benzonitrile; 2- {2-amino-5- [4 - ((3S) -3-dimethylaminopyrrolidine-1-carbonyl) -phenyl] -pyridin-3-yloxymethyl} -benzonitrile; 2- {2-amino5- [4 - ((3S) -3-amino-pyrrolidine-1-carbonyl) -phenyl] -pyridin-3-yloxymethyl} benzonitrile; 2- {2-amino-5- [4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl) phenyl] -pyridin-3-yloxymethyl} -benzonitrile; 2- {2-amino-5- [4- (4-methylpiperazine-1-carbonyl) -phenyl] -pyridin-3-yloxymethyl} -benzonitrile; 2- {5- [4- (4acetyl-piperazine-1-carbonyl) -phenyl] -2-amino-pyridin-3-yloxymethyl} benzonitrile; 4- [6-amino-5- (2-cyano-benzyloxy) -pyridin-3-yl] -N- (1-methylpiperidin-4-yl) -benzamide; 4- [6-amino-5- (2-cyano-benzyloxy) -pyridin-3-yl] (2-morpholin-4-yl-ethyl) -benzamide; 4- [6-amino-5- (2-cyano-benzyloxy) pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) -benzamide; 4- [6-amino-5 (2,4-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (2,4-dichlorobenzyloxy) -pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] methanone; {4- [6-amino-5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -

2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2,4-dichlorobenzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-dimethylamino-pyrrolidin-1-yl] methanone; {4- [6-amino-5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -

3-amino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; {4- [6-amino5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; 1- (4- {4- [6-amino-5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] Petition 870190089642, of 10/09/2019, page 38/482

34/470 benzoyl} -piperazin-1-yl) -ethanone; 4- [6-amino-5- (2,4-dichloro-benzyloxy) pyridin-3-yl] -N- (1-methyl-piperidin-4-yl) -benzamide; 4- [6-amino-5- (2,4dichloro-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) -benzamide; 4- [6 amino-5- (2,4-dichloro-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) benzamide; 4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3-yl] benzoic acid; {4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl) [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-trifluoromethyl-benzyloxy) pyridin-3-yl] -phenyl} - [(3S) -3-dimethylamino-pyrrolidin-1-yl] -methanone; [(3S) -3amino-pyrrolidin-1-yl] - {4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3yl] -phenyl} -methanone; {4- [6-amino-5- (2-trfluoromethyl-benzyloxy) -pyridin-3-yl] phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; {4- [6-amino-5- (2trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; 1- (4- {4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3-yl] benzoyl} -piperazin-1-yl) -ethanone; 4- [6-amino-5- (2-trifluoromethylbenzyloxy) -pyridin-3-yl] -N- (1-methyl-piperidin-4-yl) -benzamide; 4- [6-amino5- (2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) benzamide; 4- [6-amino-5- (2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -N- (3morpholin-4-yl-propyl) -benzamide; 4- [6-amino-5- (4- # tert! -butylbenzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (4-tert-butyl-benzyloxy) pyridin-3-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone ; {4 [6-amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (4-tert-butyl-benzyloxy) pyridin-3-yl] -phenyl} - [(3R) -3-dimethylamino-pyrrolidin-1-yl] -methanone; {4- [6 amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; 1- (4- {4- [6-amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] benzoyl} -piperazin-1-yl) -ethanone; 4- [6-amino-5- (4-tert-butyl-benzyloxy) pyridin-3-yl] -N- (1-methyl-piperidin-4-yl) -benzamide; 4- [6-amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) -benzamide; 4- [6Petition 870190089642, of 10/09/2019, p. 39/482

35/470 amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) benzamide; 4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] benzoic acid; {4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] -phenyl} [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-4-floro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) pyridin-3-yl] -phenyl} - [(3S) -3-dimethylamino-pyrrolidin-1-yl] -methanone; {4- [6 amino-5- (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3-aminopyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; 1 - (4- {4- [6-amino-5 (2-chloro-4-fluor-benzyloxy) -pyridin-3-yl] -benzoyl} -piperazin-1-yl) -ethanone;

4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-ylethyl) -benzamide; 4- [6-amino-5- (2-chloro-4-fluoro-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) -benzamide; 4- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; {4 [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin1 -yl-piperidin-1-yl) -methanone; {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-amino-piperidin-1-yl) -methanone; {4- [6 amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethylpiperazin-1-yl) -methanone; {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1- il] -methanone; {4 [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -3dimethylamino-pyrrolidin-1-yl] -methanone; {4- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3R) -3-amino-pyrrolidin-1-yl] methanone; {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] phenyl} - [(3S) -3-amino-pyrrolidin-1-yl] -methanone ; 4- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -N- (1-methyl-piperidin-4-yl) -benzamide; 4- [6 amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (2-pyrrolidin-1-ylethyl) -benzamide; 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] Petition 870190089642, of 10/09/2019, p. 40/482

36/470

N- (3-pyrrolidin-1-yl-propyl) -benzamide; 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) -benzamide; 4- [6-amino-5 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) benzamide; 3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -benzoic acid; {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] phenyl} - (4-methyl-piperazin-1-yl) -methanone; {3- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] phenyl} - (4-amino-piperidin-1-yl) -methanone; {3- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-1-yl) -methanone; {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone; {3- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -phenyl) - [(3S) -3-dimethylamino-pyrrolidin-1-yl] methanone; {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] phenyl} - [(3R) -3-amino-pyrrolidin-1-yl] -methanone ; {3- [6-amino-5- (2-chloro-

3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(3S) -amino-pyrrolidin-1-yl] methanone; 3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (1methyl-piperidin-4-yl) -benzamide; 3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (2-pyrrolidin-1-yl-ethyl) -benzamide; 3- [6-amino-5 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (3-pyrrolidin-1-yl-propyl) benzamide; 3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N (2-morpholin-4-yl-ethyl) -benzamide; 3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -N- (3-morpholin-4-yl-propyl) -benzamide; N- [2- (4acetyl-piperazin-1-yl) -ethyl] -3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -benzamide; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- [4- (1,1-dioxo1À ⁶ -isothiazolidin-2-yl) -phenyl] -pyridin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5 [4- (1,1-dioxo-1 À ⁶ -isothiazolidin-2-yl) -phenyl] -pyridin-2-ylamine; 5- [4- (1,1 dioxo-1À ⁶ -isothiazolidin-2-yl) -phenyl] -3- (2-fluoro-6-trifluoromethyl-benzyloxy) pyridin-2-ylamine; 2-Diethylamino-ethanesulfonic acid {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide; {4- [6-amino-5Petition 870190089642, of 10/09/2019, p. 41/482

37/470 2-cyclopropylamino-ethanesulfonic acid (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2-Pyrrolidin-1-ylethanesulfonic acid {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2- (4-hydroxy-piperidin-1-yl) -ethanesulfonic {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide ; 2-Morpholin-4-yl-ethanesulfonic acid {4 [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2-Piperidin-1-ylethanesulfonic acid {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2-Dimethylamino-ethanesulfonic acid {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide; 2- (4-acetyl-piperazin-1-yl) ethanesulfonic {4- [6-amino-5 (2-chloro-3,6-difluoro-benzyl} -amide; {4- [6-amino-5 2- (cyclopropylmethyl-amino) -ethanesulfonic acid (2-chloro-3,6-diflúor-benzyloxy) -pyridin-3yl] -phenyl} -amide; {4 [6-amino-5- (2-chloro- 2 - [(3R) -3-hydroxy -pyrrolidin-1-yl] -ethanesulfonic acid 3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -ethanes; {4- [6-amino- Acid 5 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide 2 - [(2S) -

2-hydroxymethyl-pyrrolidin-1-yl] -ethanesulfonic; {4- [6-amino-5- (2-chloro-

2- [4- (2-hydroxy acetyl) -piperazin-1-yl] -ethanesulfonic acid 3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -ethanesulfonic acid; 2- (4-Acetyl-piperazin-) acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide

1- il) -ethanesulfonic; 2-Pyrrolidin-1-yl-ethanesulfonic acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; Acid {3- [6 amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide

2- morpholin-4-yl-ethanesulfonic; 2-diethylaminoethanesulfonic acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2-Dimethylamino-ethanesulfonic acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide; 2piperidin-1-yl-ethanesulfonic acid {3- [6-amino-5 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; Acid 2 - [(3R) -3-hydroxymethyl {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amidePetition 870190089642, of 10 / 09/2019, p. 42/482

38/470 pyrrolidin-1-yl] -ethanesulfonic; 2- (4-hydroxy-piperidin-1-yl) ethanesulfonic {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2- [4- (2-hydroxy-acetyl) -piperazin- {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide 1-yl] ethanesulfonic; 2 - [(3R) -3-hydroxy-pyrrolidin-1- {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3yl] -phenyl} -amide il] -ethanesulfonic; 2- (cyclopropylmethyl-amino) -ethanesulfonic acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 2-Cyclopropylamino-ethanesulfonic acid {3- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (2dimethylaminomethyl-phenyl) -pyridin-2-ylamine; compound with trifluoroacetic acid; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-pyrrolidin-1-yl-phenyl) -pyridin-

2-ylamine; compound with trifluoroacetic acid; N- {4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide; compound with trifluoroacetic acid; 5- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -thiophene-2-carboxylic acid; {5- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -thiophen-2-yl} - (4-methyl-piperazin-1-yl) methanone; {5- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] thiophen-2-yl} - [(2R) -2-pyrrolidin-1-ylmethyl- pyrrolidin-1-yl] -methanone; 5- [6-Amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -thiophene-2-carboxylic acid (1-methylpiperidin-4-yl) -amide; {5- [6-amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -thiophen-2-yl} - (3,5-dimethyl-piperazin-1-yl) methanone ; 5- [6-Amino-5- (2-chloro-acid) (2-pyrrolidin-1-yl-ethyl) -amide

3,6-difluoro-benzyloxy) -pyridin-3-yl] -thiophene-2-carboxylic; {5- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -thiophen-2-yl} - (4-pyrrolidin-1-ylpiperidin-1-yl) - methanone; 4- [6-amino-5- (3-fluor-2-trifluoromethylbenzyloxy) -pyridin-3-yl] -benzoic acid; {4- [6-amino-5- (3-fluor-2-trifluoromethylbenzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; 4 {6-amino-5- (3-fluor-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -N- (1-methylpiperidin-4-yl) -benzamide; {4- [6-amino-5- (3-fluor-2-trifluoromethyl-

Petition 870190089642, of 10/09/2019, p. 43/482

39/470 benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-1-yl) -methanone; {4- [6 amino-5- (3-fluor-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - (3dimethylamino-pyrrolidin-1-yl) -methanone; {4- [6-amino-5- (3-fluor-2trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl] -methanone; 4- [6-amino-5- (3-fluor-2-trifluoromethylbenzyloxy) -pyridin-3-yl] - # N! - (2-morpholin-4-yl-ethyl) -benzamide; {4- [6-amino-

5- (3-fluor-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl) - (4-methyl-piperazin-

1- yl) -methanone; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -4- [6-amino-5- (3-fluorine-

2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -benzamide; 2piperidin-1-yl-ethanesulfonic acid (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide ; 2- (4-Hydroxy-piperidin-) acid 4- (6-amino-5- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide 1-yl) ethanesulfonic; 2-Dimethylamino-ethanesulfonic acid (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -amide; 2-Cyclopropylamino-ethanesulfonic acid (4- {6 amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide; 4- {6-amino-5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid; (4- {6-amino-5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - [(2R) -2-pyrrolidin-1-ylmethylpyrrolidin -1-yl) -methanone; 4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -M- (1-methyl-piperidin-4-yl) -benzamide ; (3- {6-amino-5- [1 (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - [(3R) -3-aminopyrrolidin-1- il)] - methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin- 1-yl) -methanone; (4- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-methylpiperazin-1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - (3,5-dimethyl-piperazin-1- il) -methanone; 2-cyclopropylamino-ethanesulfonic acid (4- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide; (4- {6-amino-5- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide of 2-dimethylamino-ethanesulfonic acid; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -etoxy] Petition 870190089642, of 10/09/2019, page 44/482

40/470 pyridin-3-yl} -phenyl) -amide of 2 - [(3R) -3-hydroxy-pyrrolidin-1-yl)] ethanesulfonic; and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00073] In another embodiment, the invention provides a compound selected from the group consisting of: 4- [5-amino-6- (2,6-dichlorobenzyloxy) -pyrazin-2-yl] -phenol; 3- (2,6-dichloro-benzyloxy) -5- [4- (1,1-dioxo1À ⁶ -isothiazolidin-2-yl) -phenyl] -pyrazin-2-ylamine; 3- (2,6-dichloro-benzyloxy) -5 [3- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrazin-2-ylamine; 3- (2,6-dichlorobenzyloxy) -5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrazin-2-ylamine; 5- (4 amino- phenyl) -3- (2,6-dichloro-benzyloxy) -pyrazin-2-ylamine; 4- [5 amino-6- (2,6-dichloro-benzyloxy) -pyrazin-2-yl] -benzoic acid; {4- [5-amino-6 (2,6-dichloro-benzyloxy) -pyrazin-2-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl] -methanone; {4- [5-amino-6- (2,6-dichloro-benzyloxy) -pyrazin-2yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; 2-Morpholin acid {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide

4-yl-ethanesulfonic; 2-Piperidin-1-yl-ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; Acid {4- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide

2- (4-hydroxy-piperidin-1-yl) -ethanesulfonic; 2-Pyrrolidin-1-ylethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; Acid {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide 2 - [(3R) -3-Hydroxyl-pyrrolidin-1- il] - ethanesulfonic; 2 - [(2S) -2-Hydroxymethyl-pyrrolidin-acid {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide il] ethanesulfonic; 2- (cyclopropylmethyl-amino) -ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide; 2-Dimethylamino-ethanesulfonic acid {4 [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2-diethylaminoethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2Petition 870190089642, of 10/09/2019, p. 45/482

41/470 yl] 2- (4-acetyl-piperazin-1-yl) -ethanesulfonic acid -phenyl} -amide; 2- [4- (2-Hydroxy-Acetyl) -piperazin {4 [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide -1-yl] -ethanesulfonic; Acid {4- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide

2-cyclopropylamino-ethanesulfonic; 2 - [(3R) -3-Hydroxymethylpyrrolidin-1-yl] {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide -ethanesulfonic; 2- (4-hydroxy-piperidin-1-yl) {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide ethanesulfonic; 2- (4-acetyl-piperazin-1-yl) -ethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide ; 2-Piperidin-1-yl-ethanesulfonic acid {3 [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2-diethylaminoethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2-morpholin-4-yl-ethanesulfonic acid {3- [5-amino-6 (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2-Pyrrolidin-1-yl-ethanesulfonic acid {3- [5-amino-6 (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2-Dimethylaminoethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 2- [4- (2-hydroxy-acetyl) -piperazin- {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide 1-yl] ethanesulfonic; 2- (cyclopropylmethyl-amino) -ethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -phenyl} -amide; 2 - [(3R) -3-hydroxy-pyrrolidin-1 {3 [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide -il] -ethanesulfonic; 2-Cyclopropylamino-ethanesulfonic acid {3- [5-amino-6 (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} -amide; 4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -benzoic acid; {4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-

1-yl] -methanone; 4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] N- (2-pyrrolidin-1-yl-ethyl) -benzamide; {4- [5-amino-6- (2-chloro-3,6-difluoro-

Petition 870190089642, of 10/09/2019, p. 46/482

42/470 benzyloxy) -pyrazin-2-yl] -phenyl} - [(3S) -3-amino-pyrrolidin-1-yl] -methanone; N [2- (4-acetyl-piperazin-1-yl) -ethyl] -4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -benzamide; 4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (3-pyrrolidin-1-yl-propyl) -benzamide; {4- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - [(3S) -3dimethylamino-pyrrolidin-1-yl] -methanone; {4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - [(3R) -3-dimethylamino-pyrrolidin-1-yl] methanone; {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] phenyl} - (3,5-dimethyl-piperazin-1-yl) -methanone; {4- [5-amino-6- (2-chloro-3,6difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; 4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (3morpholin-4-yl-propyl) -benzamide; 4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (1-methyl-piperidin-4-yl) -benzamide; 4- [5-amino-

6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (2-morpholin-4-yl-ethyl) benzamide; {4- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] phenyl} - (4-methyl-piperazin-1-yl) -methanone; 3- [5-amino-6- (2-chloro-

3,6-difluoro-benzyloxy) -pyrazin-2-yl] -benzoic acid; {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; {3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - [(3R) -3amino-pyrrolidin-1-yl] -methanone; {3- [5-amino-6- (2-chloro-3,6-diflúorbenzyloxy) -pyrazin-2-yl] -phenyl} - [(3S) -3-amino-pyrrolidin-1-yl] -methanone; {3 [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - (3,5-dimethylpiperazin-1-yl) -methanone; 3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) pyrazin-2-yl] -N- (3-morpholin-4-yl-propyl) -benzamide; (3- [6-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1yl) -methanone; {3 - [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] phenyl} - [(3S) -3-dimethylamino-pyrrolidin-1-yl] -methanone; 3 - [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (2-pyrrolidin-1-yl-ethyl) benzamide; 3- [5-amino-6 - (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N (1-methyl-piperidin-4-yl) -benzamide; {3- [5-amino-6- (2- chlorine-3,6-diflúorPetition 870190089642, of 10/09/2019, page 47/482

43/470 benzyloxy) -pyrazin-2-yl] -phenyl} - [(2S) -pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] methanone; 3- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (2morpholin-4-yl-ethyl) -benzamide; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -benzamide; 3- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -N- (3-pyrrolidin-1-ylpropyl) -benzamide; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (1 H-indol-5-yl) pyrazin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-pyrrolidin-1ylmethyl-1 H-indol-5-yl) -pyrazin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -

5- (3-diethylaminomethyl-1 H-indol-5-yl) -pyrazin-2-ylamine; 1- (4- {5- [5-amino-

6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -1 H-indol-3-ylmethyl} -piperazin-1-yl) -ethanone; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- [3- (2,6dimethyl-morpholin-4-ylmethyl) -1 H-indol-5-yl] -pyrazin-2-ylamine; N- (1- {5- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -1 H-indol-3-ylmethyl} (3S) -pyrrolidin-3 -yl) -acetamide; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3piperidin-1-ylmethyl-1 H-indol-5-yl) -pyrazin-2-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -5- (3-morpholin-4-ylmethyl-1 H-indol-5-yl) -pyrazin-2-ylamine; 3- [1 (2-chloro-3,6-difluoro-phenyl) -2-methyl-propoxy] -5- [4- (2-morpholin-4-yl-ethoxy) phenyl] -pyrazin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5- [4- (2morpholin-4-yl-ethoxy) -phenyl] -pyrazin-2-ylamine; compound with trifluoroacetic acid; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4- (2-morpholin-4-yl-ethoxy) phenyl] -pyrazin-2-ylamine; compound with trifluoroacetic acid; N- (4- {5 amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) methanesulfonamide; 2-Pyrrolidin-1-yl- (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide ethanesulfonic; 2- (4-Hydroxyl-piperidin-) acid 4- (5-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide 1-yl) -ethanesulfonic; 2piperidin-1-yl-ethanesulfonic acid (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; 2- (cyclopropylmethyl-amino) ethanesulfonic acid 4- (5-amino-6- (1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -etoxy] Petition 870190089642, of 10/09/2019, page 48/482

44/470 pyrazin-2-yl} -phenyl) -amide of 2 - [(3R) -3-HydroxyI -pyrrolidin-1-yl] ethanesulfonic acid; 2 [(2S) -2- (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide Hydroxymethyl) pyrrolidin-1-yl] ethanesulfonic; 2-Dimethylamino-ethanesulfonic acid (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide; 2-Morpholin-4-yl- (4 {5-amino-6- [1- [2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide ethanesulfonic; 2-Diethylaminoethanesulfonic acid (4- {5-amino-6- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; 2-cyclopropylamino-ethanesulfonic acid (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide; 3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} benzoic acid; (3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} phenyl - [(3S) -3-amino-phrrolidin-1 -yl) -m-ethanone; (3- {5-amino-6- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - [(3R) -3-amino-pyrrolidin-1il ) -m-ethanone; (3- {5-amino-6- (1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-

2-yl} -phenyl) - [(2R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone; N- [2- (4acetyl-piperazin-1-yl) -ethyl] -3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyrazin-2- il} -benzamide; (3- {5-amino-6- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - [(2S) -2-pyrrolidin-1 -ylmethyl-pyrrolidin-1-yl) methanone; 3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -benzoic acid; 3- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] pyrazin-2-yl} -M- (1-methyl-piperidin-4-yl) -benzamide ; 3- {5-amino-6- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-pyrrolidin-1-yl-propyl) benzamide; (3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1 -yl) -methanone; 4- [5-amino-6 (3-fluor-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] benzoic acid; 4- [5-amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] -N- (2-morpholin-4-yl-ethyl) benzamide; 4- [5-amino-6- (3-fluor-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] N- (1-methyl-piperidin-4-yl) -benzamide; and pharmaceutically acceptable salts, hydrates and solvates thereof.

Petition 870190089642, of 10/09/2019, p. 49/482

45/470 [00074] In another embodiment, the invention provides a compound selected from the group consisting of: (4- {6-amino-5- [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] -pyridine -3-yl} -phenyl) - (4-methyl-piperazin-1-yl) -methanone; N [2- (4-acetyl-piperazin-1-yl) -ethyl] -4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3 -il} -benzamide; 4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide ; 4- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-morpholin-4-yl-ethyl) benzamide; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} -phenyl) - ((S) -3-amino-pyrrolidin-1 -yl) -methanone; (4- {6-amino-5- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -3-amino-pyrrolidin-1 -yl) methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - (4-amino-piperidin-1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -3-hydroxy-pyrrolidin-1-yl) - methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - ((R) -3-hydroxy-pyrrolidin- 1-yl) -methanone; (4- {6-amino-5- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -2-hydroxymethylpyrrolidin-1-yl ) -methanone; 4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -N- (2-diethylamino-ethyl) -benzamide; 4- {6-amino-5- (1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-pyrrolidin-1-yl-ethyl) benzamide; 3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -benzoic acid; (3- {6-amino-5- [1 - (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - (4-methyl-piperazin-1-yl) -methanone; 3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (1-methyl-piperidin-4-yl) benzamide; (3- {6-amino-5 - [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-ylphenyl) - ((S) -2-pyrrolidin-1-ylmethyl) -pyrrolidin-1-yl) -methanone ; N- [2- (4-acetylpiperazin-1-yl) -ethyl] -3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3- il} -benzamide; (3- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - ((S) -3-amino-pyrrolidin- 1-yl) -methanone; 3- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (3-morpholin-4yl-propyl) -benzamide; (3- {6-amino-5- [l- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] Petition 870190089642, of 10/09/2019, page 50/482

46/470 pyridin-3-yl) -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone; 3- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-pyrrolidin-1yl-ethyl) -benzamide; 3- {6-amino-5- [2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-

3-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide; 3- {6-amino-5- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; (3- {6- amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4pyrrolidin-1-yl-piperidin-1 -yl) -methanone; 2-Diethylaminoethanesulfonic acid (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide; 2- (4-hydroxy-piperidin) (4- {6-amino-5- (1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -amide -1-yl) ethanesulfonic; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -amide 2 -piperidin-1-yl-ethanesulfonic acid (4- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide 2- (cyclopropylmethyl-amino) -ethanesulfonic; (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl) -phenyl) -amide 2 - ((R) -3HydroxyI -pyrrolidin-1-yl) -ethanesulfonic acid; 2-cyclopropylaminoethanesulfonic acid (4- {6-amino-5- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide; 2-Diethylamino-ethanesulfonic acid (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -amide; acid

4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -benzoic; 4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-morpholin-

4-yl-ethyl) -benzamide; 4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -N- (1-methyl-piperidin-4-yl) -benzamide ; (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethylpyrrolidin -1-yl) -methanone; (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) - ethoxy] -pyridin-3-yl} -phenyl} ((R) -3-amino-pyrrolidin- 1-yl) -methanone; (4- {6 amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S ) -

3,5-dimethyl-piperazin-1-yl) -methanone; 4- {6-amino-5- (1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (3-pyrrolidin-1-yl-propyl) - benzamide; (4 {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -2Petition 870190089642, de 09/10/2019, page 51/482

47/470 pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone; (4- {6-amino-5- [1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-methyl-piperazin-4-yl) methanone; (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - (4-pyrrolidin-1-yl-piperidin- 1-yl) -methanone; 4- (6-amino-5- [1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

(4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -

3-amino-pyrrolidin-1-yl) -methanone; 3- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid; (3- {6-amino-5- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl -piperazin-1-yl) methanone; (3- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - ((R) -3-amino-pyrrolidin- 1-yl) -methanone; 3- {6-amino-5- [1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (1-methyl-piperidin-4-yl) -benzamide;

(3- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4methyl-piperazin-1-yl) - methanone; 3- {6-amino-5- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyridin-3-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide; 3- {6 amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-pyrrolidin-1yl-ethyl) -benzamide; (3- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - ((S) -3-amino-pyrrolidin- 1-yl) -methanone; 3- {6-amino-5 [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-morpholin-4-yl-ethyl) benzamide; (3- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl -pyrrolidin-1-yl) -methanone; (3- {6-amino-

5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl) - methanone; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5 [4- (2-morpholin-4-yl-ethoxy) -phenyl-pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -5- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -pyridin-2ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- {4- [2- (1-methyl-pyrrolidin-2yl) -ethoxy] -phenyl} -pyridin-2- ilamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5 [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -5- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -pyridin-2-ylamine; 1- (4- {6-

Petition 870190089642, of 10/09/2019, p. 52/482

48/470 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenoxy) -3morpholin-4-yl-propan-2-ol; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4- (2-ethylamino-ethoxy) -phenyl] -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -5- [4- (1-methyl-piperidin-3-ylmethoxy) -phenyl] -pyridin-2-ylamine; 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4- (2-diisopropylamino-ethoxy) -phenyl] pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4- (1-methylpiperidin-4-yloxy) -phenyl] -pyridin-2-ylamine; N- (4- {6-amino-5- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -methanesulfonamide; 3- [1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -5- [4- (1,1-dioxo-1lambda * 6 * -isothiazolidin-2-yl) -phenyl] -pyridin-2-ylamine; N- (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -phenyl) -methanesulfonamide; 3- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -5-phenyl-pyridin-2-ylamine; N- (4- {6-amino-5 - [(R) -1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -methanesulfonamide; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-thiophen-3-yl-pyridin-2-ylamine; 5-benzo [b] thiophen-2-yl-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 4-Methyl-piperazine-1-carboxylic acid (4- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide ; 1 - (4- {6-amino-5- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -3- (2-pyrrolidin-1-yl-ethyl) -urea; 1 - (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -3- (2hydroxy-ethyl) - urea; 1- (4- {6-amino-5- (1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -3- (2-morpholin-4- yl-ethyl) -urea; (4- {6-amino-5- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide (R ) -3amino-pyrrolidine-1-carboxylic; (4- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide (S) -3-amino-pyrrolidine-1-carboxylic acid; 1- (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} - phenyl) -3- (1-methyl-piperidin-4-yl) -urea; 1 - (4- {6-amino-5- [1- (2-chloro-3,6difluor-phenyl) -ethoxy] -pyridin -3-yl} -phenyl) -3- (1-methyl-piperidin-4-yl) -urea; (4 {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide of (R) -3-amino-pyrrolidine-1-carboxylic acid; (4- {6-amino-5- [1- (2-chloro-3,6 -difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -acid acid (S) -3Petition 870190089642, of 10/09/2019, page 53/482

49/470 amino-pyrrolidine-1-carboxylic; 1 - (4- {6-amino-5- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) -3- (2-hydroxy-ethyl) - urea; 4methyl-piperazine-1-carboxylic acid (4- {6-amino-5- [1 (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -amide; 1 - (4- {6-amino-5- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) -3- (2-pyrrolidin-1-yl -ethyl) -urea; 1 - (4- {6 amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -3- (2morpholin-4-yl-ethyl )-urea; (R) -2-Pyrrolidin- (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -amide 1-ylmethyl-pyrrolidine-1-carboxylic; 3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} benzoic acid; (3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) ((3R, 5S) -3,5-dimethyl-piperazin- 1-yl) -methanone; (3- {6-amino-5- [1- (2,6dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone ; 3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2pyrrolidin-1-yl-ethyl) -benzamide; 3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] pyridin-3-yl} -N- (2-pyrrolidin-4-yl-ethyl) -benzamide; (3- {6-amino-5- [1- (2,6dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin1 -il ) -methanone; 3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N (3-pyrrolidin-1-yl-propyl) -benzamide; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3 {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -benzamide; 3- {6 amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N- (1-methyl-piperidin-4-yl) benzamide; (3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl-phenyl) (4-methyl-piperazin-1-yl) -methanone; (3- {6-amino-5- [1- (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-yl) methanone; (3- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) ((S) -3-amino-pyrrolidin-1-yl) -methanone; (3- {6-amino-5- [1- (2,6-dichlorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -3-amino-pyrrolidin-1-yl) - methanone; 4- {4-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid; 4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2-pyrrolidin-

1-yl-ethyl) -benzamide; 4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; (4- {6-amino-5- [1- (2,6-dichloro-

Petition 870190089642, of 10/09/2019, p. 54/482

50/470 phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) methanone; 4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N- (1methyl-piperidin-4-yl) -benzamide; (4- {6-amino-5- [1- (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl-piperazin- 1-yl) -methanone;

N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -4- {6-amino-5- [1- (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} -benzamide; 4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] pyridin-3-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide; (4- {6-amino-5- [1- (2,6dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) -3-aminopyrrolidin-1-yl) methanone; (4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) ((R) -3-amino-pyrrolidin-1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichlorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -yl) methanone; (4- {6-amino-5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichlorophenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-methyl-piperazin-1-yl) -methanone; (S) -2- acid (S) -2- (3- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) amide pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic; 4-Methyl-piperazine acid (3- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -amide 1-carboxylic; 4-Pyrrolidin-1-yl (3- {6-amino-5- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -amide -piperidine-1-carboxylic; (3- {6-Amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -amide (3R, 5S) -3,5-dimethyl-piperazine-1-carboxylic; 1 - (3- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -3- (1-methyl -piperidin-4-yl) -urea; 1 - (3 {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -3 (3-pyrrolidin -1-yl-propyl) -urea; 1 - (3- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -3- (2-pyrrolidin -1-yl-ethyl) -urea; 1 - (3- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -3- (2morfolin-4 -yl-ethyl) -urea; 1 - (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -prop-2-ynyl) -3- (3- morfolin-4-yl-propyl) -urea; (3- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-inyl) Petition 870190089642, of 10/09/2019 , p. 55/482

51/470 (R) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid amide; 3- [1- (2,

6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-dimethylamino-prop-1-ynyl) -pyridin-2ylamine; (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} prop-2-ynyl) -urea; N- (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop-2-ynyl) -2-piperidin-1 -yl-acetamide; N- (3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -2-morpholin-4 -ylacetamide; N- (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} -prop-2-ynyl) -2-pyrrolidin-1- yl acetamide; N- (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -2 - (( R) -3-hydroxy pyrrolidin-1-yl) -acetamide; N- (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -prop-2-ynyl) -2- (4- hydroxy-piperidin-1-yl) -acetamide; N (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -

2-dimethylamino-acetamide; N- (3- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -prop-2-ynyl) -2-diethylamino- acetamide; 2- (4-acetylpiperazin-1-yl) -N- (3- {6-amino-5- (1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} - prop-2-ynyl) -acetamide; (3- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -1,1-dimethyl- 4-methylpiperazine-1-carboxylic acid prop-2-ynyl; (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3 -il} -1,1-dimethyl-prop-2-ynyl) -3R, 5S) -3,5dimethyl-piperazine-1-carboxylic acid; (3- {6-amino-5- [1- ( 2,6-Dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -1,1-dimethyl-prop-2-ynyl) -amide (R) -2pyrrolidin-1-ylmethyl-pyrrolidine-1 -carboxylic; (3- {6-amino-5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -1,1-dimethyl-prop-2-inyl) -(S) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid amide; 1- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) - ethoxy] -pyridin-3-yl} -1,1-dimethyl-prop-2-ynyl) -3 (2-morpholin-4-yl-ethyl) -urea; 1 - (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -1,1-dimethyl-prop-2-ynyl) -3- (2-pyrrolidin-1-yl- ethyl) -urea ; (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -1,1-dimethylprop-2-ynyl) -amide 4-pyrrolidin-1-yl-piperidine-1-carboxylic acid; 3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) acid cyclohexylamide Petition 870190089642, of 10/09/2019, p. 56/482

52/470 ethoxy] -pyridin-3-yl} -propinoic; 3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl] -propinoic acid isopropylamide; 4- (3-amino-3methyl-but-1-ynyl) -2- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -phenylamine; (4- {6 amino-5- [1- (3-fluor-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4methyl-piperazin-1-yl) -methanone; (4- {6-amino-5- [1- (3-fluor-2-trifluoromethylphenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1-yl ) -methanone; (4- {6-amino-5- (1- (3-fluor-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) ((3R, 5S) -3,5-dimethyl- piperazin-1-yl) -methanone; (4- {6-amino-5- [1- (3fluor-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((S) - 2-pyrrolidin-1ylmethyl-pyrrolidin-1-yl) -methanone; (4- {6-amino-5- [1- (3-fluoro-2trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) -methanone; 4- {6-amino-5- [1- (3-fluor-2-trifluoromethyl-phenyl) ethoxy] -pyridin-3 -yl} -N- (1-methyl-piperidin-4-yl) -benzamide; 4- {6-amino-5- [1 (3-fluor-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3- yl} -N- (2-pyrrolidin-1-yl-ethyl) benzamide; 4- {6-amino-5- [1- (3-fluor-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-

3-yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; 4- {6-amino-5- [1- (3-fluoro-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -N- (3-pyrrolidin-1-yl-propyl) benzamide; 4- {6-amino-5- [1- (3-fluoro-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-

3-yl} -N- (3-morpholin-4-yl-propyl) -benzamide; 6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -nicotinonitrile; 6-amino-5- [1- (2,6-dichloro-3-cyano-phenyl) ethoxy] -nicotinonitrile; 5-aminomethyl-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-2-ylamine; (R) -2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin3-ylmethyl} -amide ; N- {6-amino-5- [1 - (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3ylmethyl} -methanesulfonamide; N- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-ylmethyl} -acetamide; N- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-ylmethyl} -4-methyl-benzenesulfonamide; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5-vinyl-pyridin-2-ylamine; (S) -1- [6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -ethan-1,2-diol; (R) -1- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -ethane-1,2-diol; 3Petition 870190089642, of 10/09/2019, p. 57/482

53/470 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (1 H-pyrazol-4-yl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [1- (2-pyrrolidin-1-yl-ethyl) -1 Hpirazol-4-yl] -pyridin-2 -the mine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [1- (2diisopropylamino-ethyl) -1 H-pyrazol-4-yl] -pyridin-2-ylamine; 3- [1- (2,6-dichloro3-fluoro-phenyl) -ethoxy] -5- [1- (2-morpholin-4-yl-ethyl) -1 H-pyrazol-4-yl] -pyridin-2ylamine ; 5-bromo-3- (3-fluoro-2-methoxy-benzyloxy) -pyridin-2-ylamine; 5bromo-3- [1- (3-fluoro-2-methoxy-phenyl) -ethoxy] -pyridin-2-ylamine; {4- [6-amino-

5- (3-fluoro-2-methoxy-benzyloxy) -pyridin-3-yl] -phenyl} ((3R, 5S) -3,5-dimethyl-piperazin-1-yl) -methanone; (4- {6-amino-5- [1- (3-fluoro-2-methoxy-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl- piperazin-1-yl) -methanone;

5-bromo-3- (3-fluoro-2-isopropoxy-benzyloxy) -pyridin-2-ylamine; {4- [6 amino-5- (3-fluoro-2-isopropoxy-benzyloxy) -pyridin-3-yl] -phenyl} - ((3R, 5S) -

3,5-dimethyl-piperazin-1-yl) -methanone; 5- (4-amino-phenyl) -3- [1- (2,6-dichloro3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; (4- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenoxy) -acetic acid methyl ester; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenoxy) -acetic acid; 2- (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] pyridin-3-yl} -phenoxy) -1 - ((3R, 5S) - 3,5-dimethyl-piperazin-1-yl) -ethanone; 2- (4 {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenoxy) -1 - ((R) 3-hydroxy -pyrrolidin-1-yl) -ethanone; 4- [2- (4 {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenoxy) tert-butyl ester -acetyl] piperazine-1-carboxylic; 2- (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -phenoxy) -1 - ((R) -2- pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) ethanone; 5-bromo-3- (3-fluoro-6,7,8,9-tetrahydro-5 H-benzocyclohepten-5yloxy) -pyridin-2-ylamine; {4- [6-amino-5- (3-fluor-6,7,8,9-tetrahydro-5 Hbenzocyclohepten-5-yloxy) -pyridin-3-yl] -phenyl} - ((3R, 5S) - 3,5-dimethylpiperazin-1-yl) -methanone; 3- (3-fluoro-6,7,8,9-tetrahydro-5Hbenzocyclohepten-5-yloxy) -5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -pyridin-2ylamine; N- {4- [6-amino-5- (3-fluoro-6,7,8,9-tetrahydro-5Hbenzocyclohepten-5-yloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide; 3- (3Petition 870190089642, of 10/09/2019, page 58/482

54/470 fluorine-6,7,8,9-tetrahydro-5 H-benzocyclohepten-5-yloxy) -5- (1 H-pyrazol-4yl) -pyridin-2-ylamine; 5-bromo-3- [1- (2-chloro-3-fluoro-phenyl) -ethoxy] -pyridin-2ylamine; 3- [1- (2-chloro-3-fluoro-phenyl) -ethoxy] -5- [4- (2-pyrrolidin-1-yl-ethoxy) phenoxy] -pyridin-2-ylamine; 5'-benzyloxy - [2,3 '] bipyridinyl-6'-ylamine; 5benzyloxy - [3,3 '] bipyridinyl-6-ylamine; 3-benzyloxy -5-pyrimidin-5-yl-pyridin-

2- amine; 5-benzyloxy - [3,3 '] bipyridinyl-6,6'-diamine; 5 '- (2-chloro-benzyloxy) [2,3'] bipyridinyl-6'-ylamine; 5- (2-chloro-benzyloxy) - [3,3 '] bipyridinyl-6-ylamine;

3- (2-chloro-benzyloxy) -5-pyrimidin-5-yl-pyridin-2-ylamine; 5- (2-chloro-benzyloxy) - [3, 3 '] bipyridinyl-6,6'-diamine; 5 '- (4-chloro-benzyloxy) - [2,3'] bipyridinyl-6'-ylamine; 5- (4-chloro-benzyloxy) - [3,3 '] bipyridinyl-6-ylamine; 3- (4-chloro-benzyloxy) -5-pyrimidin-5-yl-pyridin-2-ylamine; 5- (4-chloro-benzyloxy) [3,3 '] bipyridinyl-6,6'-diamine; 5 '- (2-chloro-3,6-difluoro-benzyloxy) [2,3'] bipyridinyl-6'-ylamine; 5- (2-chloro-3,6-difluoro-benzyloxy) - [3,3 '] bipyridinyl-6-ylamine; 5- (2-chloro-3,6-difluoro-benzyloxy) - [3,4 '] bipyridinyl-6-ylamine; 3- (2-chloro-3,6-difluoro-benzyloxy) -5-pyrimidin-5-yl-pyridin-2-ylamine; 5- (2-chloro-3,6-difluoro-benzyloxy) - [3,3 '] bipyridinyl-6,6'-diamine; 5 '- (2,6-dichlorobenzyloxy) - [2,3'] bipyridinyl-6'-ylamine; 5- (2,6-dichloro-benzyloxy) [3,3 '] bipyridinyl-6-ylamine; 5- (2,6-dichloro-benzyloxy) - [3,4 '] bipyridinyl-6ylamine; 3- (2,6-dichloro-benzyloxy) -5-pyrimidin-5-yl-pyridin-2-ylamine; 5 (2,6-dichloro-benzyloxy) - [3,3 '] bipyridinyl-6,6'-diamine; 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - [3,3 '] bipyridinyl-6,6'-diamine; {6'-amino-5 '- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] - [2,3'] bipyridinyl-4-yl} - (4-methyl-piperazin-1-yl ) methanone; {6'-amino-5 '- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [2,3'] bipyridinyl-6-yl} - (4-methyl-piperazin-1- il) -methanone; {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - [3,3'] bipyridinyl-5-yl} - (4-methyl-piperazin-1il) -methanone; {6'-amino-5 '- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - [3,3'] bipyridinyl-6-yl} - (4-methyl-piperazin-1 -yl) -methanone; {6-amino-5- [1- (2,6-dichloro3-fluoro-phenyl) -ethoxy] - [3,4 '] bipyridinyl-2'-yl} - (4-methyl-piperazin-1-yl) -methanone; 5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] - [3,3 '] bipyridinyl-6,6'-diamine; {6'amino-5 '- [l- (2-chloro-3,6-difluoro-phenyl) -ethoxy] - [2,3'] bipyridinyl-5-yl} - (4-methylPetition 870190089642, of 10 / 09/09/2019, page 59/482

55/470 piperazin-1-yl) -methanone; {6'-amino-5 '- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] - [2,3'] bipyridinyl-4-yl} - (4-methyl-piperazin-1- il) -methanone; {6'-amino5 '- [l- (2-chloro-3,6-difluoro-phenyl) -ethoxy] - [2,3'] bipyridinyl-6-yl} - (4-methylpiperazin-1-yl) - methanone; {6'-amino-5 '- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] - [3,3'] bipyridinyl-5-yl} - (4-methyl-piperazin-1- il) -methanone; {6'-amino5 '- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] - [3,3'] bipyridinyl-6-yl} - (4-methylpiperazin-1-yl) - methanone; {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] [3,4 '] bipyridinyl-2'-yl} - (4-methyl-piperazin-1-yl ) -methanone; 5 '- [1- (2,6-dichloro3-fluoro-phenyl) -ethoxy] - [2,3'] bipyridinyl-6'-ylamine; 5 '- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] - [2,3'] bipyridinyl-6'-ylamine; 5- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] - [3,3 '] bipyridinyl-6-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5pyrimidin-5-yl-pyridin-2-ylamine; {6'-amino-5 '- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - [2,3'] bipyridinyl-5-yl} - (4-methyl-piperazin-1- il) -methanone; 5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] - [3,4 '] bipyridinyl-6-ylamine; 5-benzyloxy -3- [1 (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 3- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -5- (2-ethyl-butoxy) -pyridin-2-ylamine; 3- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -5- (3-methyl-butoxy) -pyridin-2-ylamine; 3- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -5-butoxy-pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -5-propoxy-pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] -5-cyclohexylmethoxy-pyridin-2-ylamine; 6-amino-5- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyridin-3-ol; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5- (2cyclohexyl-ethoxy) -pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5isobutoxy -pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5phenethyloxy-pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -5 (pyridin-2-ylmethoxy) -pyridin-2-ylamine; 3- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] -5- (pyridin-4-ylmethoxy) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5-dimethylpiperazin -1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5- dimethyl-piperazin-1-yl) -methanone;

5- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -2-fluoroPetition 870190089642, of 10/09/2019, p. 60/482

56/470 benzonitrile; 4- (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin3-yl} -phenyl) -piperidin-4-ol; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -phenyl) -piperidin-1-yl-methanone; (4- {6-amino-5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -pyrrolidin-1-yl-methanone; 4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -3-methyl-benzoic acid methyl ester; - [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4 (dimethyl-piperazin-1-ylmethyl) -phenyl] -pyridin-2-ylamine; (4- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -3,5-dimethoxy -phenyl) - (dimethylpiperazin-1- il) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyridin-3-yl} -2-fluor-phenyl) - (dimethyl-piperazin-1- il) -methanone; (4- {6 amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -3-fluor-phenyl) (dimethyl-piperazin-1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -3-methyl-phenyl) - (dimethyl-piperazin-1-yl ) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4methyl- [1,4] diazepan- 1-yl) -methanone; (4- {6-amino-5- [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - [1,4] diazepan-1-yl-methanone ; (4- {6 amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -piperazin1 -yl-methanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-vinyl-pyridin-2ylamine; (4- {6-amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - ((3R, 4S) -3,4- dihydroxy (Pyrrolidin-1-yl) -methanone; 5 - [(1-benzylpyrrolidin-3-ylamino) -methyl] -3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2ylamine; 4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -Nazetidin-3-yl-benzamide; 4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -N, N-dimethyl-benzenesulfonamide; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (6-methoxy -1 H-benzoimidazol-2-yl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (6-methoxy -1-methyl-1 Hbenzoimidazol-2-yl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -5- [4- (4-methyl- [1,4] diazepane-1-sulfonyl) -phenyl] -pyridin-2- ilamine; 6- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin3-yl} -1-methyl-1H-indazol-3-carboxylic acid amide; 3- [1- (2,6-dichloro-3-fluoro-phenyl) Petition 870190089642, of 9/10/2019, p. 61/482

57/470 ethoxy] -5- (1-methyl-1 H-pyrazol-4-yl) -pyridin-2-ylamine; 5- (3-chloro-phenyl) -3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (4-fluoro-3-methyl-phenyl) -pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine; 3 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-fluoro-phenyl) -pyridin-2-ylamine; 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-trifluoromethoxy-phenyl) -pyridin-2ylamine; 5-benzo [1,3] dioxol-5-yl-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-2-ylamine; 3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin3-yl} -phenol; (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) -methanol; 3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} -benzonitrile; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-methoxy-phenyl) pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,5-dichlorophenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2,5dimethyl-phenyl) -pyridin-2-ylamine; 5- (5-chloro-2-methoxy-phenyl) -3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 5- (3-chloro-4-fluoro-phenyl) -3 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (5-fluoro-2-methoxy-phenyl) -pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-isopropyl-phenyl) -pyridin-2-ylamine; 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,4-dichloro-phenyl) -pyridin-2-ylamine; 4 {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -benzonitrile; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,4-difluoro-phenyl) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((2R, 6S) -2,6 -dimethyl-morpholin-4-yl) -methanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -5- (2-ethoxy-phenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -5- (2,5-dimethoxy-phenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -5- (2,4-dimethoxy-phenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2,6-dimethoxy-phenyl) -pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine; 5 (2-chloro-phenyl) -3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 3-1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2-trifluoromethoxy-phenyl) -pyridinPetition 870190089642, of 10/09/2019, p. 62/482

58/470

2ylamine; 1 - (2- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) -ethanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2-fluoro-phenyl) pyridin-2-ylamine; (2- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) -methanol; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-o-tolylpyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2-methoxy phenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2,6-dimethyl-phenyl) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -morpholin-4-yl-methanone; (4- {6-amino -5- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -2-chloro-phenyl) - ((3R, 5S) -dimethylpiperazin-1-yl) -methanone ; 4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-3-yl} -2-methyl-phenyl) - ((3R, 5S) - dimethyl-piperazin-1-yl) methanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- [4 - ((2R, 6S) -2,6dimethyl-morpholin-4-ylmethyl) -phenyl] -pyridin- 2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (4-morpholin-4-ylmethyl-phenyl) -pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,5-dimethyl-phenyl) -pyridin-2-ylamine; 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-m-tolyl-pyridin-2-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,4-dimethoxy-phenyl) -pyridin-2-ylamine; 5biphenyl-3-yl-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine; 5- (3,5bis-trifluoromethyl-phenyl) -3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,4-dichloro-phenyl) -pyridin-

2-ylamine; 1- (3- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} -phenyl) -ethanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3,5-difluoro-phenyl) -pyridin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (2,5dichloro-phenyl) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2,6-dichloro-4trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - ((3R, 5S) -3,5-dimethylpiperazin -1-yl) -methanone; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (3-ethoxy-phenyl) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2-trifluoromethyl-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - (3,5-dimethyl-piperazin-1-yl) -methanone; (4- {6-amino-5 [1- (3-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (3,5-dimethyl-piperazin-1yl) -methanone; 7- [4- (3,5-dimethyl-piperazine-1-carbonyl) -phenyl] -2-phenyl-4 HPetition 870190089642, of 10/09/2019, p. 63/482

59/470 pyrido [3,2-b] [1,4] oxazin-3-one; {4- [6-amino-5- (3-fluor-2-trifluoromethylbenzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-1-yl) -methanone; {4- [6 amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-

1-yl) -methanone; [4- (6-amino-5-benzyloxy-pyridin-3-yl) -phenyl] - (3,5-dimethyl-piperazin-1-yl) -methanone; (4- {6-amino-5- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] -pyridin-3-yl} -phenyl) - (4-ethyl-piperazin-1-yl) -methanone; [4- (6-amino-5benzyloxy-pyridin-3-yl) -phenyl] - (4-ethyl-piperazin-1-yl) -methanone; {4- [6 amino-5- (2-methyl-benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-1-yl) methanone; 3- {2-amino-5- [4- (4-pyrrolidin-1-ylpiperidine-1-carbonyl) -phenyl] -pyridin-3-yloxymethyl} -benzoic acid methyl ester; 3- {2-amino-5- [4- (3,5-dimethyl-piperazine-1-carbonyl) -phenyl] pyridin-3-yloxymethyl} -benzoic acid methyl ester; {4- [6-amino-5- (2-methyl-benzyloxy) -pyridin-3yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; [4- (6-amino-5cyclohexylmethoxy-pyridin-3-yl) -phenyl] - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; 4- (1- {2-amino-5- [4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl) phenyl] -pyridin-3-yloxy} -ethyl) - [2- (3-hydroxy -phenyl) -ethyl] -benzamide; 4- (1- {2 amino-5- [4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl) -phenyl] -pyridin-3-yloxy} ethyl) - [2- (2,6-dichloro -phenyl) -ethyl] -benzamide; 4- (1- {2-amino-5- [4- (4pyrrolidin-1-yl-piperidine-1-carbonyl) -phenyl] -pyridin-3-yloxy} -ethyl) - (1-benzylpiperidin-4-yl ) -benzamide; 4- (1- {2-amino-5- [4- (4-pyrrolidin-1-ylpiperidine-1-carbonyl) -phenyl] -pyridin-3-yloxy} -ethyl) -3- (2-oxo-pyrrolidin -1-yl) propyl-benzamide; (4- {6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - (4-ethyl-piperazin-1-yl) -methanone; {4- [6-amino-5- (2,6dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - (3,5-dimethyl-piperazin-1-yl) -methanone; (6-amino-3-aza-bicyclo [3.1.0] hex-3-yl) - (4- {6-amino-5- [1- (2,6-dichloro-3fluor-phenyl) -etoxy] - pyridin-3-yl} -phenyl) -methanone; 5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -6 '- (2-morpholin-4-yl-ethoxy) -3,3'] bipyridinyl-6-ylamine; 6'-amino5 '- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -1- (2-pyrrolidin-1-yl-ethyl) -1 H- [3,3'] bipyridinyl -6-one; 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -6 '- (2-pyrrolidin-1-ylethoxy) - [3,3'] bipyridinyl-6-ylamine; 6'-amino-5 '- [1- (2,6-dichloro-3-fluoro-phenyl) Petition 870190089642, of 10/09/2019, p. 64/482

60/470 ethoxy] -1- [2- (1-methyl-pyrrolidin-2-yl) -ethyl] -1 H- [3,3 '] bipyridinyl-6-one; (4- {6 amino-5- [1- (2,4,6-trimethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-ylpiperidin-1-yl) - methanone; (4- {6-amino-5- [1- (2-chloro-6-fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1- il) -methanone; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (4-fluoro-phenyl) -pyridin-2-ylamine; 6'-amino-5 '[1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -1 H- [3,3'] bipyridinyl-6-one; 5'-bromo5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - [3,3 '] bipyridinyl-6-ylamine; 3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -5- (4-dimethylamino-phenyl) -pyridin-2-ylamine; 5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -2'-methoxy - [3,3 '] bipyridinyl-6-ylamine;

3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (1 H-indol-5-yl) -pyridin-2-ylamine; (4- {6-amino-5- [1- (2,6-dichloro-phenyl) -propoxy] -pyridin-3-yl} -phenyl) - (3,5-dimethyl-piperazin-1-yl) -methanone; [4- (6-amino-5-benzyloxy-pyridin-3-yl) phenyl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; 3- (2,6-dichloro-3-fluorobenzyloxy) -5-thiazol-2-yl-pyridin-2-ylamine; (4- {6-amino-5- [1- (2-fluor-6-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1il ) -methanone; 3- (2,6-dichloro-3-fluoro-benzyloxy) -5- (1-methyl-1H-imidazol-2yl) -pyridin-2-ylamine; {4- [6-amino-5- (2,4,6-trimethyl-benzyloxy) -pyridin-3-yl] phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; {4- [6-amino-5- (2,3,5,6tetramethyl-benzyloxy) -pyridin-3-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; {4- [6-amino-5- (2,4,6-trifluor-benzyloxy) -pyridin-3-yl] -phenyl} - (4pyrrolidin-1-yl-piperidin-1-yl) -methanone; (4- {6-amino-5- [1- (2-fluor-6trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1yl) - methanone; 6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -N-methylnicotinamidine; 6-amino-5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -N- (2morpholin-4-yl-ethyl) -nicotinamidine; (4- {6-amino-5- [1- (2,4,5-trifluor-phenyl) propoxy] -pyridin-3-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1- il) -methanone; (4 {6-amino-5- [1- (6-chloro-2-fluor-3-methyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4pyrrolidin-1-yl-piperidin- 1-yl) -methanone; 3- (1- {2-amino-5- [4- (4pyrrolidin-1-yl-piperidine-1-carbonyl) -phenyl] -pyridin-3-yloxy} -ethyl) -benzoic acid; and pharmaceutically acceptable salts, hydrates and solvates thereof.

Petition 870190089642, of 10/09/2019, p. 65/482

61/470 [00075] In another embodiment, the invention provides a compound selected from the group consisting of: 3- {5-amino-6- [1- (2,6-dichloro-3 fluoro-phenyl) -ethoxy] -pyrazin- 2-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide; 3- {5 amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-pyrrolidin-1yl-propyl) -benzamide; 3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -N- (1-methyl-piperidin-4-yl) -benzamide ; 3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-pyrrolidin-1-yl-ethyl) lbenzamide; 3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] 3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin- 2-yl} -benzamide; (3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - (4methyl-piperazin-1-yl) - methanone; (3 {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - (4-pyrrolidin-1-yl-piperidin-1- il) -methanone; (3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((3R, 5S) -3.5 -dimethyl-piperazin-1-yl) -methanone; (3- {5-amino-6- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -2-pyrrolidin-1-ylmethyl -prrrolidin-

1- yl) -methanone; (3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-

2-yl} -phenyl) - ((R) -3-amino-pyrrolidin-1-yl) -methanone; (3- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -3-amino-pyrrolidin -1yl) -methanone; 4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -benzoic acid; 4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyrazin-2-yl} -N- (3-pyrrolidin-1-yl-propyl) -benzamide ; (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - (4-methyl-piperazin-1-yl) methanone ; (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} phenyl) - (4-pyrrolidin-1-yl-piperidin- 1-yl) -methanone; 4- {5-amino-6- [1- (2-chloro-

3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl-piperazin-

1- yl) -methanone; (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-

2-yl} -phenyl) - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone; (4- {5- amino-6- [1- (2-chloro-3,6-difluor-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((R) -2pyrrolidin-1-ylmethyl -pyrrolidin-1-yl) -methanone; (4- {5-amino-6- (1- (2-chloroPetition 870190089642, from 10/09/2019, page 66/482

62/470

3.6- difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((R) -3-amino-pyrrolidin-1-yl) - methanone; 4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} N- (1-methyl-piperidin-4-yl) -benzamide ; 4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-pyrrolidin-1-yl-ethyl) -benzamide; 4- {5 amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-morpholin-4yl-ethyl) -benzamide; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -4- {5-amino-6- [1- (2chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2 -il} -benzamide; 2- [4- (2-hydroxy-acetyl) -piperazin-1-yl] -ethanesulfonic acid (4- {5-amino-6- [1- (2-chloro-

3.6- difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; 3- [5-amino-6- (3-fluor-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] -benzoic acid; {3- [5-amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] -phenyl} - (4-pyrrolidin-1-ylpiperidin-1-yl) -methanone; 3- [5-amino-6- (3-fluor-2-trifluoromethylbenzyloxy) -pyrazin-2-yl] -N- {2- [ethyl- (2-methoxy-ethyl) -amino] -ethyl} -benzamide; {3- [5-amino-6- (3-fluor-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] -phenyl} - (4methyl-piperazin-1-yl) -methanone; 3- [5-amino-6- (3-fluor-2-trifluoromethylbenzyloxy) -pyrazin-2-yl] -N- (3-pyrrolidin-1-yl-propyl) -benzamide; N- [2- (4acetyl-piperazin-1-yl) -ethyl] -3- [5-amino-6- (3-fluor-2-trifluoromethylbenzyloxy) -pyrazin-2-yl] -benzamide; {4- [5-amino-6- (3-fluor-2trifluoromethyl-benzyloxy) -pyrazin-2-yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) methanone; {4- [5-amino-6- (3-fluor-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] phenyl} - (4-methyl-piperazin-1-yl) -methanone; {4- [5-amino-6- (3-fluor-2trifluoromethyl-benzyloxy) -pyrazin-2-yl] -phenyl} - ((S) -2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) -methanone; (3- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyrazin-2-yl} -phenyl) - (4-methyl-piperazin-1-yl) -methanone; (3- {5-amino-

6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl-piperazin-1-yl ) -methanone; 3- {5-amino-6- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin-2-yl} -N- (1-methyl-piperidin-4-yl) -benzamide; 3- {5 amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-pyrrolidin-1yl-ethyl) -benzamide; 3- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] pyrazin-2-yl} -N- (2-morpholin-4-yl-ethyl) -benzamide ; 3- {5-amino-6- [1- (2,6Petition 870190089642, from 10/09/2019, page 67/482

63/470 dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-morpholin-4-yl-propyl) benzamide; (3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -phenyl) - (4-cyclopropylamino-piperidin-1-yl) - methanone; 3- {5-amino-6- [1 (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -N - ((S) -2-hydroxy -3-morpholin-

4-yl-propyl) -benzamide; 3- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyrazin-2-yl} -N - ((R) -2-hydroxy -3-pyrrolidin- 1-yl-propyl) -benzamide; (3- {6- amino-5- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (4pyrrolidin-1-yl-piperidin-1 -yl) -methanone; 2-Diethylaminoethanesulfonic acid (4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; 2- (4-hydroxy-piperidin) (4- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide -1-yl) ethanesulfonic; 2-Dimethylamino-ethanesulfonic acid (4- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) -amide; 2 - ((R) -3 acid (4 {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide -HydroxyI -pyrrolidin-1-yl) -ethanesulfonic; (4- {5-amino-

6- Pyrrolidin-1-yl) -ethanesulfonic acid 6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -ethanesulfonic acid; 4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -benzoic acid; 4- {5-amino-6- [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] -pyrazin-2-yl} -N - ((R) -2-hydroxy -3-pyrrolidin-1 -yl-propyl) benzamide; (4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -phenyl) - (4-cyclopropylamino-piperidin-1-yl) - methanone; 4- {5-amino-6- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N - ((S) -2-hydroxy -3-pyrrolidin1 - yl-propyl) -benzamide; 4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyrazin-2-yl} -N - ((R) -2-hydroxy -3-morpholin- 4-yl-propyl) -benzamide; 4- {5 amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (1-methylpiperidin-4-yl) -benzamide; (4- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -2-pyrrolidin-1- ilmethyl-pyrrolidin-1-yl) methanone; (4- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} phenyl) - (4-pyrrolidin-1-yl-piperidin- 1-yl) -methanone; 4- {5-amino-6- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-morpholin-4-yl-ethyl) Petition 870190089642, of 10/09/2019, p. 68/482

64/470 benzamide; (4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -phenyl) - (4-methyl-piperazin-1-yl) - methanone; (4- {5-amino-6- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((3R, 5S) -3,5-dimethyl-piperazin-1-yl) -methanone; 4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2yl} -benzoic acid; (4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; 4- {5-amino-6- [1- (2,6-dichlorophenyl) -ethoxy] -pyrazin-2-yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; (4- {5-amino-

6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl) -phenyl) - ((3R, 5S) -3,5-dimethyl-piperazin-1-yl) -methanone; 4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] pyrazin-2-yl} -N- (1-methyl-piperidin-4-yl) -benzamide; (4- {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-

1-yl) -methanone; (4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} phenyl) - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-yl) -methanone; (4- {5-amino-6 [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - (4-methyl-piperazin-1-yl) methanone; (4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) ((R) -3-aminopyrrolidin-1-yl) -methanone ; (4- {5 amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -3aminopyrrolidin-1-yl) - hydrogen chloride - methanone; 4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-pyrrolidin-1-yl-ethyl) -benzamide; 4- {5-amino-6- [1 (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-pyrrolidin-1-yl-propyl) benzamide; 3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} benzoic acid; 3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -N (1-methyl-piperidin-4-yl) -benzamide; 3- {5-amino-6- [1- (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} -N- (2-pyrrolidin-1-yl-ethyl) -benzamide; (3- {5-amino-6- [1 (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((3R, 5S) -3,5-dimethylpiperazin-1- il) -methanone; 3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] pyrazin-2-yl} -N- (2-morpholin-4-yl-ethyl) -benzamide; (3- {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-

1-yl) -methanone; (3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} phenyl) - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone; N- [2- (4-acetyl-piperazin-

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1-yl) -ethyl] -4- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} benzamide; N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl } -benzamide; (3- {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin1 -il ) -methanone; 3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -N (3-pyrrolidin-1-yl-propyl) -benzamide; (3- {5-amino-6- (1- (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} -phenyl) - ((S) -3-amino-pyrrolidin-1-yl) -methanone; (3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} phenyl) hydrochloride salt - ((R) -3-amino -pyrrolidin-1-yl) -methanone; (3- {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) - (4-methyl-piperazin -1-yl) -methanone;

1- (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -3 (2-morpholin-4- il-ethyl) -urea; (R) -2-Pyrrolidin (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide -1-ylmethylpyrrolidine-1-carboxylic; 1 - (4- {5-amino-6- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] -pyrazin-2-yl} -phenyl) -3- (2-pyrrolidin-1- il-ethyl) -urea; 4-methyl-piperazine-1-carboxylic acid (4- {5-amino-6- [1 (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide; 1 - (4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -3- (2-hydroxy-ethyl) - urea; (S) -3amino-pyrrolidine (4- {5-amino-6- [1 (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide 1-carboxylic; 1 - (4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -3- (1-methyl-piperidin-4 -il) -urea; 4-Methyl-piperazine-1-carboxylic acid (4- {5 amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amide ; 1- (4- {5-amino-6- [1- (2,6-dichloro-

3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -3- (2-hydroxy-ethyl) -urea; (4- {5- Amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -amino acid (S) -3-amino -pyrrolidine-1-carboxylic; 1 - (4- {5-amino-6- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) -3- (1-methyl-piperidin-4 -il) urea; 5- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] thiophene-2-carboxylic acid; {5- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) pyrazin-2-yl] -thiophen-2-yl} - (4-methyl-piperazin-1-yl) -methanone ; {5- [5-amino-6Petition 870190089642, of 10/09/2019, p. 70/482

66/470 (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -thiophen-2-yl} - (4-pyrrolidin-1-ylpiperidin-1-yl) -methanone; {5- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) pyrazin-2-yl] -thiophen-2-yl} - ((3R, 5S) -3,5-dimethyl- piperazin-1-yl) -methanone; {5- [5-amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -thiophen-2-yl} - ((R) -

2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone; 5- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -thiophene-2-carboxylic acid (2-morpholin-4-yl-ethyl) -amide ; 3- [1- (2,6-dichloro-3fluorophenyl) ethoxy] -5- {5 - [(4-methylpiperazin-1-yl) carbonyl] pyridin-2-yl} pyrazin- trifluoroacetate

2-amine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-pyridin-4-yl-pyrazin-2-ylamine; 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (1 H-pyrrol-2-yl) -pyrazin-2ylamine; (6- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} pyridin-3-yl) - (4-methyl-piperazin- 1-yl) -methanone; (2- {5-amino-6- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -pyridin-4-yl) - (4-methyl-piperazin-1il ) -methanone; (6- {5-amino-6- [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2yl} -pyridin-2-yl) - (4-methyl-piperazin-1 -yl) -methanone; (5- {5-amino-6- [1- (2,6dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -pyridin-3-yl) - (4-methyl-piperazin-1il ) -methanone; (4- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -pyridin-2-yl) - (4-methyl-piperazin-1 -yl) -methanone; 6- {5-amino-6- (1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (2-morpholin-4-yl-ethyl) nicotinamide; 5 - {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -N- (2-morpholin-4-yl-ethyl) -nicotinamide; 6 - {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-morpholin-4-yl-propyl) -nicotinamide; 5 {5-amino-6 [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyrazin-2-yl} -N- (3-morpholin-

4-yl-propyl) -nicotinamide; 6- {5-amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) - ethoxy] -pyrazin-2-yl} -pyridin-3-yl) - (4-isopropyl-piperazin- 1-yl) -methanone; and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00076] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 1 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00077] In another aspect, the invention provides a selected compound

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67/470 part of the group consisting of the compounds shown in Table 2 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00078] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 3 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00079] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 4 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00080] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 5 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00081] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 6 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00082] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 7 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00083] In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 8 and pharmaceutically acceptable salts, hydrates and solvates thereof.

[00084] In another embodiment, the invention provides compounds having the following chemical structure (Formula 6):

_R 23

R ²¹

Arila <^

NH ₂ where,

Z is CH or N;

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Aryl is an optionally fused aryl or an optionally fused heteroaryl group that is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR ²⁴ , -COR ²⁴ , -COOR ²⁴ , -CONR ²⁴ R ²⁵ , -CN, -NO2, -S (O) mR ²⁴ , SO2NR ²⁴ R ²⁵ , perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl, -NR ²⁴ R ²⁵ , -NR ²⁴ C (O) R ²⁵ and -NR ²⁴ S (O) pR ²⁵ ;

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, halogen, -COR ²⁴ , -COOR ²⁴ , -CONR ²⁴ R ²⁵ , -CN, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, and aryl;

R ²³ is selected from the group consisting of:

an optionally fused aryl, heteroaryl, alicyclic or heterocyclic group, optionally substituted by one or more substituents selected from the group consisting of a halogen, - (CH2) nOR ²⁴ , -COR ²⁴ , -COOR ²⁴ , -CONR ²⁴ R ²⁵ , - CN, -NO2, -S (O) mR ²⁴ , SO2NR ²⁴ R ²⁵ , perfluoroalkyl, -O-perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, heteroaryl, alkenyl, alkynyl, aryl, - (CH2) nNR ²⁴ R ²⁵ , - NR ²⁴ C (O) R ²⁵ and -NR ²⁴ S (O) pR ²⁵ , wherein said heterocycle, heteroaryl and aryl substituents can be optionally substituted by a group selected from the group consisting of lower alkyl, halogen, -C ( O) NR ²⁴ R ²⁵ , NR ²⁴ R ²⁵ , NR ²⁴ C (O) R ²⁵ and

NR ²⁴ S (O) pR ²⁵ ;

-OR ²⁴ , -COR ²⁴ , -COOR ²⁴ , -CN, -NO2, -S (O) mR ²⁴ , SO2NR ²⁴ R ²⁵ , perfluoroalkyl, cycloalkyl, heterocycle, alkenyl, and alkynyl;

R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl, alkylaminocycloalkyl, dialkylaminoalkyl and - (CH2) n-heterocycle, in which the referred - (CH2) n-heterocycle can also be replaced by one or more alkyl

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69/470 lower, - (CH2) n-hydroxy, heterocycle and -C (O) R ²⁶ , or R24 and R25 can combine to form a 5- to 6-membered heterocyclic ring having one or more heteroatoms selected from the group consisting of in N, O, S, S (O) and SO2, said 5- to 6-membered heterocyclic ring can be optionally substituted by lower alkyl, - (CH2) n-heterocycle, cycloalkyl, halo, (CH2) nNR ²⁶ R ²⁷ , amino, -C (O) R ²⁶ , -NR ²⁶ -C (O) OR ²⁷ and -NR ²⁶ -C (O) R ²⁷ ;

wherein R ²⁶ and R ²⁷ are independently selected from the group consisting of hydrogen, lower alkyl, - (CH2) n-cycloalkyl and -C (O) - (CH2) n-OH;

except that when Z is N and R ²¹ and R ²² are H and Arila is chlorophenyl, R ²³ is not piperazine;

m is 0, 1 or 2;

n is 0, 1,2 or 3;

p is 1 or 2;

or a pharmaceutically acceptable salt thereof.

[00085] In a preferred aspect of this embodiment, in the compound of Formula (6), R ²³ is aryl or heteroaryl.

[00086] In another preferred aspect of this modality, when Z is N, R ²³ is not heteroalicyclic.

[00087] In another embodiment, the invention provides a pharmaceutical composition comprising any of the inventive compounds described herein. In particular aspects of this embodiment, the pharmaceutical composition comprises a compound of formula 1, a compound of formula 2, a compound of formula 3, a compound of formula 4, a compound of formula 5, a compound of formula 6, or a salt, hydrate or solvate, pharmaceutically acceptable thereof, as described above. In other particular aspects of this modality, the pharmaceutical composition comprises a compound selected from the compounds shown in Table 1, a compound selected from

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70/470 compounds shown in the Table compounds shown in the Table compounds shown in the Table

2, a compound selected from all

3, a compound selected from all

4, a compound selected from the compounds shown in Table 5, a compound selected from the compounds shown in Table 6, a compound selected from the compounds shown in Table 7, a compound selected from the compounds shown in Table 8, or a pharmaceutically salt, hydrate or solvate acceptable of these.

[00088] Preferred compounds of the invention include those having a c-MET inhibitory activity as defined by any one or more of IC50, Ki, or percent inhibition. Someone skilled in the art can easily determine whether a compound has such activity by performing the appropriate test. In one embodiment, particularly preferred compounds have an IC 50 of c-MET of less than 5 pM, or less than 2 pM, or less than 1 pM, or less than 500 nM, or less than 400 nM, or less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 50 nM. In another embodiment, particularly preferred compounds have a Ki of c-MET of less than 5 pM or less than 2 pM, or less than 1 pM, or less than 500 nM, or less than 400 nM, or less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 50 nM. In another embodiment, particularly preferred compounds have a c-MET inhibition of less than 1 pM of at least 10% or at least 20% 'or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%.

[00089] In another embodiment, the invention provides a process for preparing the compound of Formula (6), comprising:

(i) bromination of a compound of the formula (a):

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to provide a compound of formula (b)

Br

NH ₂ (ii) react (b) with a boronic acid or ester derivative of the formula R23B (OR) 2 in the presence of a palladium catalyst;

where R is hydrogen or an alcohol protecting group and Aryl, R ²¹ , R ²² , and R ²³ are as defined above.

[00090] In another embodiment, F is aryl or heteroaryl.

[00091] In another embodiment the invention provides a method of treating an individual for a condition for which inhibition of Met receptor tyrosine kinase is indicated, comprising administering to the individual a therapeutically effective amount of any inventive compounds described herein.

[00092] The chemical formulas mentioned here can exhibit structural tautomerism and isomerism phenomena. This invention encompasses any structural tautomeric or isomeric form and mixtures thereof which have the ability to modulate RTK, CTK and / or STK activity and are not limited to any structural tautomeric or isomeric form.

[00093] In addition, the formulas referred to here may also exhibit stereoisomerism, in which these compounds may adopt a competition 870190089642, of 10/09/2019, p. 76/482

72/470 figuration R or S in chiral centers. Therefore, this invention also covers any stereoisomeric form, its corresponding enantiomers (I or (+) and (-) isomers and diastereomers thereof, and mixtures thereof, which have the ability to modulate RTK, CTK and / or activity STK and is not limited to any stereoisomeric form.

[00094] In particular embodiments, the compound is chosen from the compounds in Tables 1 to 8.

[00095] Another embodiment of the invention relates to a method of treating an individual suffering from a condition for which protein kinase inhibition is indicated, comprising administering to the individual a therapeutically effective amount of any of the inventive compounds described herein.

[00096] Another aspect of this invention relates to a method for modulating the catalytic activity of a PK by contacting a PK with a compound of this invention or or a physiologically acceptable salt thereof.

[00097] Another aspect of this invention is that the modulation of the catalytic activity of PKs using the compound of this invention can be carried out in vitro or in vivo.

[00098] Yet another aspect of this invention is that the protein kinase whose catalytic activity is being modulated by a compound of this invention is selected from the group consisting of receptor protein tyrosine kinases, cellular tyrosine kinases and serine threonine kinases.

[00099] It is an aspect of this invention that the tyrosine protein kinase receptor whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRa, PDGFRp, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR / Flk-1, Fit-1, FGFR-1R, FGFR-2R, FGFR-3R,

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FGFR-4R, MET, DDR-1 and DDR-2.

[000100] Furthermore, it is an aspect of this invention that cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes / Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.

[000101] Another aspect of this invention is that the serine-threonine protein kinase vhose catalytic activitY is modulated by a compound of this invention is selected from the group consisting of CDi, Raf, NEK and BUBI.

[000102] Another aspect of this invention relates to a method for treating or preventing a protein kinase-related disorder in an organism comprising administering a therapeutically effective amount of any inventive compounds described herein to an organism, such as a mammal, particularly a human .

[000103] It is an aspect of this invention that the protein kinase related disorder referenced above is selected from the group consisting of a protein tyrosine kinase receptor disorder, a cellular tyrosine kinase disorder and a serine threonine kinase related disorder.

[000104] In yet another aspect of this invention, the aforementioned protein kinase-related disorder is selected from the group consisting of a Met-related disorder, an AUR2-related disorder, a ZC1-related disorder, a PDGFR-related disorder, a IGFR-related disorder and a fik-related disorder.

[000105] The aforementioned protein kinase related disorders include by way of example and not limitation, cancers such as lung cancer, NSCLC (non-small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer gives

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74/470 head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (for example, uterine sarcomas, tube carcinoma fallopian tube, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (for example, cancer of the thyroid, parathyroid or adrenal glands) soft tissue sarcomas, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, solid childhood tumors, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancies, central nervous system neoplasms (eg primary CNS lymphoma, spinal axis tumors, brain stem glioma or aden pituitary omas), blood cancers such as acute myeloid leukemia, chronic myeloid leukemia, etc., Barrett's esophagus (pre-malignant syndrome), neoplastic skin disease, psoriasis, fungal mycoses and benign prostatic hypertrophy, diabetes-related diseases such as diabetic retinopathy , retinal ischemia and retinal neovascularization, liver cirrhosis, cardiovascular disease such as atherosclerosis, immune disease such as autoimmune disease and kidney disease. Preferably, the disease is cancer such as acute myeloid leukemia and colorectal cancer.

[000106] The protein kinase-related disorder referenced above also includes disorders selected from the group consisting of diabetes, a hyperproliferative disorder, hyperproliferative kidney disorders, von HippeI - Lindau disease, restenosis, fibrosis, psoriasis, osteoarthritis, arthritis rheumatoid, an inflammatory disorder and angiogenesis in yet another aspect of this invention.

[000107] Additional disorders that can be treated or prevented

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75/470 employing the compounds of this invention are immunological disorders such as autoimmune diseases (for example, AIDS, lupus, etc.) and cardiovascular disorders such as atherosclerosis.

[000108] It is an aspect of this invention that the protein kinase related disorder being treated or prevented by administering a compound of this invention is a met kinase related disorder.

[000109] The organism in which the protein kinase related disorder is being treated or prevented is a human being in yet another aspect of this invention.

[000110] It is also an aspect of this invention that a compound described herein, or its salt, can be combined with other chemotherapeutic agents for the treatment of the diseases and disorders described above. For example, a compound or salt of this invention can be combined with alkylating agents such as fluorouracil (5-FU) alone or in another combination with leukovorin; or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, alkyl sulfonates, for example, busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; aziridines, for example, benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, for example, altretamine, triethylene melamine, triethylenephosphoramide, triethylene thiophosphoramide and trimethylolmelamine; and nitrogen mustard, for example, chlorambucil (used to treat chronic lymphocytic leukemia, macroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used to treat Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer , lung cancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembriquine, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis,

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76/470 non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); and triazines, for example, dacarbazine (used to treat soft tissue sarcoma).

[000111] Likewise a compound or salt of this invention can be expected to have a beneficial effect in combination with other antimetabolic chemotherapeutic agents such as, without limitation, folic acid analogs, for example methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, cancer of mycosis fungoids, head and neck cancer and osteogenic sarcoma) and pteropterin; and purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic leukemias, acute lymphocytes and chronic granulocytes.

[000112] The compound or salt of this invention can also be expected to provide efficacy in combination with chemotherapeutic agents based on natural product such as, without limitation, vinca alkaloids, for example, vinblastine (used in the treatment of breast and testicular cancer) ), vincristine and vindesine; epipodophyllotoxins, for example, etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; antibiotic chemotherapeutic agents, for example, daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervical, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used to treat skin cancer, esophagus and genitourinary tract); and enzymatic chemotherapeutic agents such as L-asparaginase.

[000113] In addition to the above, a compound or salt of this invention can be expected to have a beneficial effect employed in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, for example, procarbazine; adrenocortical suppressors, for example,

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77/470 mitotane, aminoglutetimide; and hormone and hormone antagonists such as adrenocorticosteroids (for example, prednisone), progestins (for example, hydroxyprogesterone caproate); estrogens (for example, diethylstilbesterol); antiestrogens such as tamoxifen; androgens, for example, testosterone propionate; and aromatase inhibitors (such as anastrozole).

[000114] Finally, the combination of a compound of this invention can be expected to be particularly effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute (non-lymphocytic) myelogenous leukemia.

[000115] The above method can be performed in combination with a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, agenes antiangiogenics such as MMP-2, MMP-9 and COX-2 inhibitors; and antI - androgens.

[000116] Examples of useful COX-II inhibitors include VIOXX ^TM , CELEBREX ^TM (alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published 24 October 1996), WO 96/27583 (published March 7 , 1996), European Patent Application No. 97304971.1 (filed on 8 july 1997), European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 (published on January 29, 1998), WO 98/34918 (published on August 14, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published in July 13, 1994), Publishes

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78/470 European Patent Application 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published 21 october 1999), WO 99/29667 (published 17 June 1999), PCT International Application No. PCT / IB98 / 01113 (filed 21 july 1998), European Patent Application No 99302232.1 (filed March 25, 1999), Great Britain Patent Application number 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60 / 148,464 (filed August 12, 1999) , United States Patent No. 5,863,949 (issued on January 26, 1999), United States Patent No. 5,861,510 (issued on January 19, 1999), and European Patent Publication 780,386 (published on December 25, 1999). June 1997), all of which are incorporated here in their entirety by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibiting activity. Most preferred are those that selectively inhibit MMP-2 and / or MMP-9 over other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP -7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[000117] Some specific examples of useful MMP inhibitors in a present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds mentioned in the following list: 3 - [[4- (4-fluorophenoxy) acid -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] propionic; hydroxyamide of 3-exo-3- [4- (4-fluoro-phenoxy) benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid; (2R, 3R) 1- [4- (2-chloro-4-fluoro-benzyloxy) benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -tetrahydropyran-4-carboxylic acid hydroxyamide; 3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid; acid hydroxyamide 4 Petition 870190089642, of 10/09/2019, p. 83/482

79/470 [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic; (R) 3- [4- (4-chloro-phenoxy) benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (4-fluoro-2-methyl-benzyloxy) -benzene sulfonyl] -3hydroxy -3-methyl-pip eridine-2-carboxylic acid hydroxyamide; 3 - [[4- (4-fluoro-phenoxy) benzenessulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid; 3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyletrahydro-pyran-4-yl) -amino] -propionic acid; hydroxyamide of 3-exo-

3-4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicycles [3.2.1] octane-

3-carboxylic; hydroxyamide of 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid; and (R) 3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts and solvates of said compounds.

[000118] Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, can also be employed in the present invention.

[000119] A compound of the invention can also be employed with signal transduction inhibitors, such as agents that can inhibit responses to EGFR (epidermal growth factor receptor), such as EGFR antibodies, EGF antibodies, and molecules that are inhibitors EGFR; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as antibodies or organic molecules that bind to the erbB2 receptor, for example, HERCEPTING (Genentech, Inc. of South San Francisco, Calif., USA). EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998 ), and United States Patent No. 5,747,498 (issued May 5, 1998), and such substances can be used in

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80/470 feels the invention described here.

[000120] EGFR inhibiting agents include, but are not limited to, monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, NY, USA), compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX447 (Medarex Inc. of Annandale, NJ, USA), and OLX-103 (Merck & Co.of Whitehouse Station, NJ, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc of Hopkinton, Mass.).

[000121] These and other EGFR inhibiting agents can be employed in the present invention.

[000122] VEGF inhibitors, for example 3- (2,4-Dimethylpyrrol-5yl) methylene-2-indolinone, (2-diethylamino-ethyl) - 5- (5-Fluorine-acid) amide

2-oxo-1,2-dihydro-indol-3-ylidenomethyl) - 2,4-dimethyl-1 H-pyrrole-3-carboxylic acid, 3- [2,4-dimethyl-5-oxo-1,2- dihydroindol-3-ylidenomethyl) -1 H-pyrrol-3-yl-propionic (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with an inventive compound described here. VEGF inhibitors are described, for example, in WO 99/24440, PCT International Application No. PCT / IB99 / 00797 (filed May 3, 1999), WO95 / 21613, WO 99/61422 (published on 2 December 1999), United States Patent No. 5,834,504 (issued November 10, 1998), WO 01/60814, WO 02/04407, WO98 / 50356, United States Patent No. 5,883,113 (issued in March 16, 1999), United States Patent No. 5,886,020 (issued March 23, 1999), United States Patent No. 5,792,783 (issued August 11, 1998), WO 99/10349 ( published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998) , WO 98/02438 (published on January 22, 1998), WO 99/16755 (published on April 8, 1999), and WO 98/02437 (published on January 22, 1999)

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81/470 January 1998), all of which are incorporated herein in their entirety by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); monoclonal anti-VEGF antibody from Genentech, Inc. of South San Francisco, Calif .; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be employed in the present invention as described herein.

[000123] These ErbB2 receptor inhibitors, such as GW282974 (Glaxo Welcome pic), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc.of TheWoodlands, Tex., USA) and 2B-1 (Chiron), can therefore be combined with any compound of the inventive compounds described herein, for example those listed in WO98 / 02434 (published on January 22, 1998), WO 99/35146 (published on July 15, 1999), WO 99/35132 (published in July 15, 1999), WO 98/02437 (published on January 22, 1998), WO 97/13760 (published on April 17, 1997), WO 95/19970 (published on July 27, 1995), Patent United States Patent No. 5,587,458 (issued December 24, 1996), and United States Patent No. 5,877,305 (issued March 2, 1999), which are all incorporated herein in their entirety by reference. ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60 / 117,341, filed January 27, 1999, and United States Provisional Application No. 60 / 117,346, filed January 27 1999, both of which are incorporated in their entirety here by reference. The erbB2 receptor inhibitor compounds and substances described in the aforementioned PCT applications, United States Patented, and United States Interim Applications, as well as other compounds and substances that inhibit the erbB2 receptor,

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82/470 can be used with the inventive compounds described here. [000124] The inventive compounds described here can also be used with other agents useful in the treatment of cancer, including, but not limited to agents capable of enhancing anti-tumor immune responses, such as CTLA4 antibodies (cytotoxic lymphocyte antigen 4), and other agents able to block CTLA4; and anti-proliferative agents such as farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the Background section, United States Patent No. 6,258,824 B1. The specific CTLA4 antibodies that can be employed in the present invention include those described in United States Provisional Application 60 / 113,647 (filed December 23, 1998) which is incorporated by reference in its entirety, however, other CTLA4 anticopros may be employed in the present invention.

[000125] The above method can also be performed in combination with radiation therapy, where the amount of the inventive compound in combination with radiation therapy is effective in treating the aforementioned diseases. Techniques for administering radiation therapy are known in the art, and these techniques can be employed in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.

[000126] Another aspect of the invention is directed to the use of any of the inventive compounds described herein in the preparation of a medicament, which is useful in the treatment of a disease mediated by abnormal Met kinase activity, such as cancer.

DETAILED DESCRIPTION

Definitions [000127] The terms pyridine and pyrazine refer to the following structures 870190089642, of 10/09/2019, p. 87/482

83/470 tures respectively:

[000128] Pharmaceutically acceptable salt or pharmaceutically acceptable salt of these 'refer to those salts which maintain the biological properties and efficacy of free bases and which are obtained by reaction with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, glyconic acid, glutamic acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, mucoic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like.

[000129] A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[000130] As used herein, physiologically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not nullify the biological activity and properties of the compound administered.

[000131] An excipient refers to an inert substance added to a pharmaceutical composition to also facilitate the administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of

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84/470 starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. [000132] Compounds that have the same molecular formula, but differ in the nature or binding sequence of their atoms or dispositions of their atoms in space are called isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereomers and those that are mirror images not overlapping each other are called enantiomers. When a compound has an asymmetric center, for example, it is linked to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by Cahn and Prelog's R and S sequencing standards, or by the way in which the molecule rotates the polarized light plane and designated as dextrogiratory or levogiratory (that is, as isomers (+) or (-) respectively). A chiral compound can exist as either an individual enantiomer or a mixture thereof. A mixture containing igau ratios of the enantiomers is called a racemic mixture.

[000133] The compounds of this invention can have one or more asymmetric centers; such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or different, of these. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the description in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 1992).

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85/470 [000134] The inventive compounds here can exhibit the phenomena of tautomerism and structural isomerism. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which have the ability to modulate RTK, CTK and / or STK activity and are not limited to any structural tautomeric or isomeric form.

[000135] It is contemplated that an inventive compound as described herein is metabolized by enzymes in the body of the body such as a human being to generate a metabolite that can modulate the activity of protein kinases. Such metabolites are within the scope of the present invention.

[000136] As used herein, PK refers to the receptor protein tyrosine kinase (RTKs), non-receptor or cell tyrosine kinase (CTKs) and serine threonine kinases (STKs).

[000137] The term method refers to the ways, methods, techniques and procedures to perform a particular task including, but not limited to those ways, methods, techniques and procedures or known to, or easily developed in, ways, methods, techniques and procedures known to practitioners of chemical, pharmaceutical, biological, biochemical and medical techniques.

[000138] As used herein, the term modulation or modulating refers to the change in the catalytic activity of RTKs, CTKs and STKs. In particular, modulation refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the astikvation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt at which RTK, CTK or STK the inhibition of the catalytic activity of RTKs, CTKs and STKs is exposed, or more preferably.

[000139] The term catalytic activity as used here refers to the tyrosine phosphorylation rate under the influence, direct or indirect,

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86/470 of RTKs and / or CTKs or the phosphorylation of serine and threonine under the influence, directly or indirectly, of STKs.

[000140] The term contact as used herein refers to the bridging of a compound of this invention and a target PK together, in such a way that the compound can affect the catalytic activity of PK, or directly, that is, interacting with the kinase itself, or indirectly, that is, interacting with another molecule on which the catalytic activity of the kinase is dependent. Such contact can be made in vitro, that is, in a test tube, a petri dish, or the like. In a test tube, the contact may involve only one compound and one PK of interest or it may involve whole cells. The cells can also be maintained or grown in cell culture plates and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before the use of the compounds in vivo with more complex living organisms is experienced. For cells outside the organism, there are multiple methods, and are well known to those skilled in the art, for putting PKs in contact with compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrying techniques.

[000141] In vitro refers to procedures performed in an artificial environment such as, for example, without limitation, in a test tube or culture medium. The skilled technician will understand that, for example, an isolated PK can be contacted with a modulator in an in vitro environment. Alternatively, an isolated cell can be contacted with a modulator in an in vitro environment.

[000142] As used herein, in vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat, rabbit, ungulate, bovine, equine, porcine, canine,

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87/470 feline, primate, or human.

[000143] As used herein, PK-related disorder, PK-controlled disorder and abnormal PK activity all refer to a condition characterized by inappropriate activity, that is, sub or, more commonly, higher, PK activity, where the particular PK it can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as a result of any of these: (1) PK expression in cells that do not normally express PKs, (2) increased PK expression inducing unwanted cell proliferation, differentiation and / or growth, or, ( 3) decreased PK expression inducing unwanted reductions in proliferation, differentiation and / or cell growth. Higher activity of a PK refers to the amplification of the gene encoding a particular PK or production of a level of PK activity that can correlate with a disorder of cell proliferation, differentiation and / or growth (that is, when the level of PK increases, the severity of one or more of the symptoms of the cell disorder increases). Underactivity is, in fact, the reverse, where the severity of one or more symptoms of cell disorder increases when the level of PK activity decreases.

[000144] As used herein, the terms prevent, prevent and prevent refer to a method of blocking an organism from acquiring a PK-related disorder in the first place.

[000145] As used herein, the terms treat, treating and treatment refer to a method of alleviating or canceling a cell disorder mediated by PK and / or its accompanying symptoms. With particular regard to cancer, these terms simply mean that the life expectancy of an individual affected by cancer will be increased or that one or more of the symptoms of the disease will be reduced.

[000146] The term organism refers to any living entity

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88/470 comprised of at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal. In a preferred aspect, the organism is a mammal. In a particularly preferred aspect, the mammal is a human being.

[000147] The term therapeutically effective amount as used herein refers to that amount of the compound being administered that will mitigate to some extent one or more of the symptoms of the disorder being treated. In reference to cancer treatment, a therapeutically effective amount refers to that amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting (i.e., delaying to a certain extent, preferably stopping) tumor metastasis , (3) inhibit to some extent (i.e., delay to a certain extent, preferably stop) tumor growth, and / or, (4) mitigate to some extent (or preferably, eliminate) one or more symptoms associated with cancer .

[000148] By monitoring it is understood to observe or detect the effect of contact of a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a naturally binding partner. Techniques for observing or detecting such effects are well known in the art. For example, the catalytic activity of a PK can be observed by determining the rate or amount of phosphorylation of a target molecule.

[000149] Reference to compounds of the invention include pharmaceutically acceptable salts, solvates and hydrates thereof.

[000150] Cell phenotype refers to the outer appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, growth

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89/470 to cell, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well known in the art. [000151] A naturally binding partner refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in the propagation of a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with PK can manifest itself as an increased or decreased concentration of the natural binding complex / PK and, as a result, in an observable change in the ability of PK to mediate signal transduction.

[000152] As used herein, administering or administering refers to the release of a compound or salt of the present invention or a pharmaceutical composition containing a compound or salt of this invention to an organism for the purpose of preventing or treating a disorder related to PK.

[000153] A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[000154] Pharmaceutically acceptable excipient refers to an inert substance added to a composition to also facilitate the administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[000155] Pharmaceutically acceptable salt refers to those salts

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90/470 that maintain the properties and biological effectiveness of the parent compound. Such salts include:

(1) acid addition salt obtained by reacting the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acid acetic, oxalic acid, malic acid (D) or (L), maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, cholic acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or malic acid (L); and (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[000156] The inventive compounds described herein can act as a prodrug. A prodrug refers to an agent, which is converted to a drug origin in vivo. Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions on the parent drug.

Indications [000157] PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine threonine kinases (STKs). Signal transduction

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91/470 mediated by RTK, is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of intrinsic protein tyrosine kinase activities and phosphorylation. The binding sites are thus created for intracellular signal transduction molecules and induce the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (for example, cell division, metabolic effects on the extracellular microenvironment, etc. ). See, Schlessinger and Allrich, Neuron, 9: 303-391 (1992).

[000158] Tyrosine phosphorylation sites on growth factor receptors have been shown to function as high affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl et al., Cell, 69: 413-423 (1992), Songyang et al., Mol. Cell. Biol., 14: 2777-2785 (1994), Songyang et al., Cell, 72: 767-778 (1993), and Koch et al., Science, 252: 668678 (1991). Several intracellular substrate proteins that associate with RTKs have been identified. They can be divided into two main groups: (1) substrates that have a catalytic domain, and (2) substrates that do not, but that serve as adapters and associate with catalytically active molecules. Songyang et al., Cell, 72: 767-778 (1993). The specificity of the interactions between the receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in binding affinities between SH2 domains and the amino acid sequences surrounding phosphotyrosine residues in particular receptors are consistent with the differences observed in their substrate phosphorylation profiles. Songyang et al., Cell, 72: 767-778 (1993). These observations suggest that the function of each RTK is determined not only by its expression pattern and availability of ligand, but also by the

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92/470 arrangement of downstream signal transduction trails that are activated by a particular receiver. Thus, phosphorylation provides an important regulatory step that determines the selectivity of signaling trails restored by specific growth factor receptors, as well as differentiation factor receptors.

[000159] STKs, being primarily cytosolic, affect the cell's internal biochemistry, often as a downline response to a PTK event. STKs have been implicated in the signaling process that initiates DNA synthesis and subsequent mitosis inducing cell proliferation.

[000160] Therefore, PK signal transduction, among other responses, cell proliferation, differentiation, growth and metabolism. Abnormal cell proliferation can result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and / or vasculogenesis.

[000161] A precise understanding of the mechanism by which the compounds of the invention, in particular, the compounds generated in vivo from the compounds of the invention, inhibit PKs is not required in order to practice the present invention. However, while not being bound by any particular mechanism or theory, the compounds are believed to interact with amino acids in the catalytic region of PKs. PKs typically have a lobed bI structure in which ATP appears to bind in the gap between the two lobes in a region where amino acids are conserved between PKs. PKs inhibitors are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region as ATP previously

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93/470 mentioned is linked to the PKs. More specifically, the compounds of this invention are supposed to bind in the general space normally occupied by the ATP adenine ring.

[000162] In another aspect, protein kinase, the catalytic activity of which is modulated by contact with a compound of this invention, is a protein tyrosine kinase, more particularly, a receptor protein tyrosine kinase. Among receptor protein tyrosine kinases whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, selected from the group consisting of Met, FIlk, FGFR, PDGFR, HER, IR, IGF, IRR, CSFIR, C-Kit, C-fms, fit. In a preferred aspect, the receptor tyrosine kinase protein whose catalytic activity can be modulated with a compound of this invention, or salt thereof.

[000163] The protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt thereof, can also be a cellular or non-receptor protein tyrosine kinase (CTK). Therefore, the catalytic activity of CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jais, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Aur2 and Yrk can be modulated by contact with a compound or salt of this invention.

[000164] Yet another group of PKs that can have their catalytic activity modulated by contact with a compound of this invention are serine-threonine protein kinases such as, without limitation, CDK2, Raf, NEK (including NEK 4a, NEK 4b, NEK 5 and NEK 6) and BUB1.

[000165] In another aspect, this invention relates to a method for treating or preventing a PK-related disorder by administering a therapeutically effective amount of a compound of this invention, or its salt, to an organism.

[000166] It is also an aspect of this invention that a pharmaceutical composition containing a compound of this invention, or a salt

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94/470 is administered to an organism for the purpose of preventing or treating a PK-related disorder.

[000167] This invention is therefore directed to compounds that modulate the PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and / or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds that modulate RTK, CTK and / or STK-mediated signal transduction trails as a therapeutic method to cure many types of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma, cancers such as lung cancer, NSCLC (non-small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma or intraocular, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (eg, uterine sarcomas, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the system endocrine ma (eg cancer of the thyroid, parathyroid or adrenal glands), soft tissue sarcomas, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, solid childhood tumors, lymphocytic lymphomas, bladder cancer , cancer of the kidneys or ureter (for example, renal cell carcinoma, renal pelvis carcinoma), pediatric malignancy, neoplasms of the central nervous system (for example, primary CNS lymphoma, spinal axis tumors, brain stem glioma or pituitary), blood cancers such as acute myeloid leukemia, chronic myeloid leukemia, etc., Barrett's esophagus (pre-malignant syndrome), neoplastic skin disease,

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95/470 psoriasis, fungal mycoses and benign prostatic hypertrophy, diabetes related diseases such as diabetic retinopathy, retinal ischemia and retinal neovascularization, liver cirrhosis, cardiovascular disease such as atherosclerosis, immune disease such as autoimmune disease and kidney disease. Preferably, the disease is cancer such as acute myeloid leukemia and colorectal cancer.

[000168] Other examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders, metabolic disorders and infectious diseases.

[000169] Cell proliferative disorders, which can be prevented, treated or also studied by the present invention include cancer, proliferative disorders of the blood vessel and proliferative disorders of the mesangial cell.

[000170] Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and angiogenesis (expansion of blood vessels). While vasculogenesis and angiogenesis play important roles in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a key role in cancer development, where they result in the formation of new capillaries needed to keep a tumor alive. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and eye diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.

[000171] Vasculogenesis and normal angiogenesis play a role in

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96/470 important skin in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and reproductive processes in females such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy. Folkman & Shing, J. Biological Chem., 267 (16): 10931-10934 (1992). Uncontrolled vasculogenesis and / or angiogenesis has been associated with diseases such as diabetes as well as solid malignant tumors that rely on vascularity for growth. Klagsburn & Soker, Current Biology, 3 (10): 699-702 (1993); Folkham, J. Natl. Cancer Inst, 82: 4-6 (1991); Weidner, and another, New Engl. J. Med., 324: 1-5 (1991).

[000172] As currently understood, the role of VEGF in endothelial cell proliferation and migration during angiogenesis and vasculogenesis indicates an important role for the KDR / FLK-1 receptor in these processes. Diseases such as diabetes mellitus (Folkman, 198, at the 11th Congress of Thrombosis and Hemostasis (Verstraeta, et al. Eds.), Pp. 583-596, Leuven University Press, Leuven) and arthritis, as well as malignant tumor growth can result of uncontrolled angiogenesis. See for example, Folkman, M Engl. J. Med., 285: 1182-1186 (1971). The receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and / or angiogenesis and a variety of serious diseases that involve cell growth caused by such processes. Plowman, and another, DN&P, 7 (6): 334-339 (1994). More particularly, the highly specific role of KDR / FLK-1 receptors in neovascularization makes them a target of choice for therapeutic methods for the treatment of cancer and other diseases that involve the uncontrolled formation of blood vessels. Therefore, an aspect of the present invention relates to compounds capable of regulating and / or modulating tyrosine kinase signal transduction including

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97/470 KDR / FLK-1 receptor signal transduction to inhibit or promote angiogenesis and / or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the KDR / FLK-1 transduced signal when activated by ligands such as VEGF. While the compounds of the present invention are believed to act on a receptor or other component along with the tyrosine kinase signal transduction pathway, they can also act directly on tumor cells that result from uncontrolled angiogenesis.

[000173] Therefore, in one aspect, this invention is directed to compounds that regulate, modulate and / or inhibit vsculogenesis and / or angiogenesis by affecting the enzymatic activity of the KDR / FLK-1 receptor and interfering with the signal transmitted by KDR / FLK-1. In another aspect, the present invention is directed to compounds that regulate, modulate and / or inhibit the KDR / FLK-1 mediated signal transduction pathway as a therapeutic method in the treatment of many types of solid tumors including, but not limited to , glioblastoma, melanoma and Kaposi's sarcoma, and carcinoma of ovary, lung, breast, prostate, pancreatic, colon and epidermoid. In addition, data suggest the administration of compounds that inhibit the signal transduction pathway mediated by KDR / Flk-1 can also be used in the treatment of hemangioma, restenosis and diabetic retinopathy.

[000174] Another aspect of this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-I receptor.

[000175] Receptor tyrosine kinase-mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of intrinsic tyrosine kinase protein activity and autophosphorylation. The binding sites are thus created by intracellular signal transduction molecules that induce the formation of complexes

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98/470 with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response, for example, cell division and metabolic effects for the extracellular microenvironment. See, Schlessinger and Ullrich, Neuron, 9: 1-20 (1992).

[000176] The intimate homology of the KDR / FLK1 intracellular regions with that of the PDGF-β receptor (50.3% homology) and / or the related fit-I receptor indicates the induction of overlap signal transduction trails . For example, for the PDGF-P receptor, members of the src family (Twamley et al., Proc. Natl. Acad. Sci. USA, 90: 7696-7700 (1993)), phosphatidylinositol-3'-kinase (Hu and others , Mol. Cell. Biol., 12: 981-990 (1992), phospholipase c _Y (Kashishian & Cooper, Mol. Cell. Biol., 4: 49- 51 (1993)), rasGTPase activating protein, (Kashishian and others, EMBO J., 11: 1373-1382 (1992), PTPID / syp (Kazlauskas et al., Proc. Natl. Acad. Sci. USA, 90: 69396943 (1993)), Grb2 (Arvidsson et al., Mol. Cell . Biol., 14: 6715-6726 (1994)), and the adapter molecules Shc and Nck (Nishimura et al., Mol. Cell. Biol., 13: 6889-6896 (1993)), have been shown to bind to regions involving different auto-phosphorylation sites. See generally, Claesson-Welsh, Prog. Growth Factor Res., 5: 37- 54 (1994). Therefore, it is likely that KDR / FLK-1 activated signal transduction trails include the ras trail (Rozakis et al., Nature, 360: 689-692 (1992)), the PI - 3'-kinase, the mediated path r src is mediated by plcy. Each of these trillions may play a critical role in the angiogenic and / or vasculogenic effect of KDR / FLK-1 on endothelial cells. Consequently, yet another aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis when such processes are controlled by these paths.

[000177] On the contrary, disorders related to the shrinking, contraction or closing of blood vessels, such as restenosis,

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99/470 are also implicated and can be treated or prevented by the methods of this invention.

[000178] Fibrotic disorders refer to the abnormal formation of extracellular mast cells. Examples of fibrotic disorders include liver cirrhosis and mesangial cell proliferative disorders. Liver cirrhosis is characterized by an increase in extracellular matrix constituents resulting in the formation of a liver scar. An enlarged extracellular matrix resulting in a liver scar can also be caused by a viral infection such as hepatitis. Lipocytes appear to play a major role in liver cirrhosis. Other fibrotic disorders involved include atherosclerosis.

[000179] Mesangial cell proliferative disorders refer to disorders caused by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as such disorders as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. RTG PDGFRs have been implicated in maintaining mesangial cell proliferation. Floege et al., Kidney International, 43: 47S- 54S (1993).

[000180] Many cancers are cell proliferative disorders and, as previously noted, PKs have been associated with cell proliferative disorders. Thus, it is not surprising that PKs such as, for example, members of the RTK family have been associated with the development of cancer. Some of these receptors, such as EGFR (Tuzi et al., Br. J. Cancer, 63: 227- 233 (1991), Torp et al., APMIS, 100: 713-719 (1992)) HER2 / neu (Slamon et al., Science , 244: 707-712 (1989)) and PDGF-R (Kumabe et al., Oncogene, 7: 627633 (1992)) are overexpressed in many tumors and / or persistently activated by autocrine loops. In fact, in the most common cancers

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100/470 common and severe these receptor overexpressions (Akbasak and SunerAkbasak et al., J. Neurol. Sci., 111: 119-133 (1992), Dickson et al., Cancer Treatment Res., 61: 249- 273 (1992) , Korc et al., J. Clin. Invest., 90: 1352-1360 (1992)) and autocrine loops (Lee and Donoghue, J. Cell. Biol., 118: 1057-1070 (1992), Korcet and others, supra , Akbasak and Suner-Akbasak and others, supra) have been demonstrated. For example, EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer. PDGFR has been associated with glioblastoma and melanoma as well as lung, ovarian and prostate cancer. RTK cmet has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas. For example, c-met has been linked to leukemia. Overexpression of the c-met gene was also detected in patients with Hodgkins disease and Burkitts disease.

[000181] IGF-IR, in addition to being involved in nutritional support and in type-II diabetes, was also associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several types of tumors, for example, human breast cancer carcinoma cells (Arteaga et al., J. Clin. Invest, 84: 1418-1423 (1989) ) and small lung tumor cells (Macauley et al., Cancer Res., 50: 2511-2517 (1990)). In addition, IGF-I, while fully involved in normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist and another, Cancer Res., 53: 2475-2478 (1993). The importance of IGF-IR and its ligands in cell proliferation is also underlined by the fact that many cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T lymphocytes, myeloid cells, chondrocytes and

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101/470 osteoblasts (bone marrow stem cells)) are stimulated to grow by IGF-I. Goldring and Goldring, Eukaryotic Gene Expression, 1: 301-326 (1991). In a series of recent publications, Baserga suggests that IGF-IR plays a central role in the mechanism of transformation and, as such, may be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, Cancer Res., 55: 249-252 (1995), Baserga, Cell, 79: 927930 (1994), Coppola et al., Mol. Cell. Biol., 14: 4588-4595 (1994). [000182] STKs have been implicated in many types of cancer including, notably, breast cancer (Cance, et al., Int. J. Cancer, 54: 571-77 (1993)).

[000183] The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, development of atheromatous plaque, Alzheimer's disease, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated for healing of horny and dermal wounds. Defects in Insulin-R and IGF-1R are indicated in type II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications mentioned in Plowman and another, DN&P, 7: 334-339 (1994).

[000184] As previously noted, not only RTKs, but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, Ick, blk, hck, fgr, AUR1, AUR2 and yrk (reviewed by Bolen et al., FASEB J., 6: 3403-3409 (1992)) are involved in the proliferative and metabolic signal transduction pathway and can thus be expected, and shown, to be involved in many PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp60 ^v-src ) in

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102/470 chicken. In addition, its cellular counterpart, the pp60 ^c-crc proto-oncogene transmits oncogenic signals from many receptors. Overexpression of EGFR or HER2 / neu in tumors induces the constitutive activation of pp60 ^c-src , which is characteristic of malignant cells but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src due to osteoclast and a possible involvement in related disorders.

[000185] Similarly, Zap70 has been implicated in T cell signaling that can be related to autoimmune disorders.

[000186] STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hyperproliferation disorders, such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.

[000187] PKs have also been implicated in embryo implantation. Therefore, the compounds of this invention can provide an effective method of preventing such an embryo implant and thereby be useful as birth control agents.

[000188] In yet another aspect, the compounds of the present invention can also be used as anti-infectious agents. [000189] Finally, both RTKs and CTKs are currently suspected of being involved in hyperimmune disorders.

Pharmaceutical Compositions and Use [000190] A compound of the present invention, or a physiologically acceptable salt thereof, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the above materials are mixed with carriers or excipient (s). Techniques for formulating and administering drugs can be found in Remington's Pharmacological Sciences, Mack Publishing Co., Easton, PA, latest issue.

Administration Routines

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103/470 [000191] Suitable administration routines may include, without limitation, intramuscular, epicutaneous, parenteral, subcutaneous, transdermal, intramedullary, intrathecal, intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, intramuscular, intradural, intrarespiratory, intrarespiratory, intrarespiratory, intrarespiral, intrarespiratory or intraocular, or nasal inhalation. Preferred administration routines are oral and parenteral.

[000192] Alternatively, one can administer the compound in a local rather than systemic manner, for example, by injecting the compound directly into a solid tumor, often in a depot or prolonged-release formulation.

[000193] In addition, someone can administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. Liposomes will be targeted to and selectively absorbed by the tumor.

Composition / Formulation [000194] The pharmaceutical compositions of the present invention can be manufactured by processes well known in the art, for example, by means of conventional mixing, dissolving, granulating, drug preparation, levigation, emulsification, encapsulation, seizure, lyophilization processes , or spray drying.

[000195] The pharmaceutical compositions for use in the methods of the present invention can be prepared by any methods of pharmacy, but all methods include the step of bringing in association the active ingredient with the carrier that constitutes one or more necessary ingredients. In particular, pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner employing one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds in preparations that can be used pharmaceutically. Appropriate formulation is

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104/470 dependent on the chosen administration routine.

[000196] Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, plasters, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastels, plasters, lotions, discs, suppositories, nasal sprays orals, aerosols and the like.

[000197] For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers, such buffers with or without a low concentration of surfactant or cosolvent, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are employed in the formulation. Such penetrants are generally known in the art.

[000198] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, pastas, suspensions and the like, for oral ingestion by a patient. Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain pill or tablet cores. Useful excipients are, in particular, fillers such as sugars, including preparations of lactose, sucrose, mannitol or sorbitol, cellulose, such as, for example, corn starch, wheat starch, rice starch and potato starch and other materials such as gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrole / ouna (PVP). If desired, disintegrating agents can be added, such as

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105/470 cross-linked polyvinylpyrrolidone, agar, or alginic acid. A salt such as sodium alginate can also be used.

[000199] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be employed which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the coatings of tablets or pills for identification or to characterize different combinations of doses of active compounds. [000200] Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and / or lubricant such as talc or magnesium stearate and, optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as oils, liquid pasrafine, liquid polyethylene glycols, cremophor, capmul, mono-, di- or medium- or long-chain triglycerides. Stabilizers can be added to these formulations as well.

[000201] For administration by inhalation, the compounds for use according to the present invention are conveniently released in the form of an aerosol spray using a pressurized package or a suitable nebulizer and propellant, for example, without limitation, dichlorodifluoromethane, trichlorofluoromethane , dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a controlled amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator

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106/470 must be formulated containing a mixture of powder of the compound and a suitable powder base such as lactose or starch.

[000202] The compounds can also be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Injection formulations can be presented in unit dosage form, for example, in ampoules or in multi - dose containers, with an added condom. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulation materials such as suspending, stabilizing and / or dispersing agents.

[000203] Pharmaceutical compositions for parenteral administration include aqueous solutions in a water-soluble form, such as, without limitation, a salt, of the active compound. In addition, suspensions of the active compounds can be prepared in a lipophilic vehicle. Suitable lipophilic carriers include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain suitable stabilizers and / or agents that increase the solubility of the compounds to provide for the preparation of highly concentrated solutions.

[000204] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[000205] The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository bases, such as cocoa butter or other glycerides.

[000206] In addition to the formulations described above, the composites

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107/470 tos can also be formulated as deposit preparations. Such long-acting formulations can be administered by implant (for example, subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention can be formulated for this administration routine with suitable polymeric or hydrophobic materials (for example, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a moderately soluble derivative such as, without limitation , a moderately soluble salt.

[000207] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, certain organic solvents such as dimethyl sulfoxide can also be used, although often at the cost of increased toxicity.

[000208] Additionally, the compounds can be released using an extended release system, such as semipermeable spans of solid hydrophobic polymers containing the therapeutic agent. Various extended release materials have been established and are well known to those skilled in the art. The extended-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to more than 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[000209] The pharmaceutical compositions here may also comprise suitable gel phase carriers or excipients or solids. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as

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108/470 polyethylene glycols.

[000210] Many of the PK modulating compounds of the invention can be provided as physiologically acceptable salts where the claimed compound can form the negatively or positively charged species. Examples of such in which the compound forms the positively charged portion include, without limitation, quaternary ammonium (defined elsewhere here), salts such as hydrochloride, sulfate, malate, carbonate, lactate, tartrate, maleate, succinate, where the atom nitrogen of the quaternary ammonium group is a nitrogen of the selected compound of this invention that reacted with the appropriate acid. Those in which a compound of this invention forms negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts, formed by reacting a carboxylic acid group in the compound with an appropriate base (for example, sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) 2), etc.).

Dosage [000211] Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount sufficient to achieve the intended purpose, that is, the modulation of PK activity or the treatment or prevention of a disorder related to PK.

[000212] More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate the symptoms of disease or prolong the survival of the individual being treated.

[000213] The determination of a therapeutically effective amount is well included in the capacity of those skilled in the art, especially taking into account the detailed description provided here.

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109/470 [000214] For any compound employed in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from cell culture assays. Thereafter, the dosage can be formulated for use in animal models to obtain a circulating concentration range that includes the IC50 as determined in cell culture (ie, the concentration of the test compound that obtains half the maximum inhibition of the activity of PK). Such information can then be used to more precisely determine useful doses in humans.

[000215] The toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in experimental cell cultures or asnimals, for example, by determining the IC50 and LD50 (both of which are described elsewhere here) for a compound object. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range for use in humans. The dosage may vary depending on the dosage form employed and the administration routine used. The exact formulation, routine of administration and dosage can be chosen by the individual doctor in view of the patient's condition. (See, for example, Fingl, et al., 1975, in The Pharmacological Basis of Therapeutics, Chapter 1 p. 1).

[000216] The dosage amount and interval can be individually adjusted to provide plasma levels of the active species that are sufficient to maintain the effects of kinase modulation. These plasma levels are referred to as minimum effective concentrations (MECs). The MEC will vary for each compound, however it can be estimated from in vitro data, for example, the concentration necessary to obtain 50 to 90% inhibition of a kinase can be verified using the assays described here. Dosages required to obtain MEC will depend on individual characteristics and administration routine

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110/470 traction. HPLC assays or bioassays can be used to determine plasma concentrations.

[000217] Dosage Intervals can also be determined using the MEC value. The compounds should be administered using a regimen that maintains plasma levels above the ECM for 10 to 90% of the time, preferably between 30 and 90% and more preferably between 50 to 90%. At present, the therapeutically effective amounts of the inventive compounds described herein can range from approximately 25 mg / m ² to 1000 mg / m ² per day. Even more preferably 25 mg / m ² to 150 mg / m ² .

[000218] In cases of local administration or selective absorption, the effective local concentration of the drug cannot be related to the plasma concentrations and other procedures known in the art can be used to determine the correct dosage amount and interval.

[000219] The amount of a composition administered, in fact, will depend on the individual being treated, the severity of the affliction, the manner of administration, the diagnosis of the prescribing physician, etc.

Packaging [000220] The compositions may, if desired, be presented in a package or dispersing device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister package. The package or dispensing device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use and sale of pharmaceuticals, whose notice reflects approval by the

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111/470 agency of the form of the compositions or of human or veterinary administration. Such a notice, for example, may be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product supplement. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of a tumor, inhibition of asngiogenesis, treatment of fibrosis, diabetes, and the like.

EXAMPLES [000221] The following examples are mentioned to illustrate the present invention. It should be understood, however, that the invention is not limited to the specific conditions and details described in these examples.

[000222] The numbering in the examples corresponds to the numbering in the included Tables. The reaction schemes and example numbers starting with the letter (I) refer to pyridine compounds, while those starting with the letter (II) refer to pyrazine compounds. Sample numbers starting with the letter L are library summaries. Example numbers having a letter notation (a, b, c, etc.) illustrate the synthesis of reagents subsequently employed in the synthesis of the inventive compounds, which have a number notation (1, 2, 3, etc.). Reagents can be synthesized as shown here, or are available from commercial sources (for example, Aldrich, Milwaukee, WI; Acros, Morris Plains, NJ; Biosynth International, Naperville, IL; Frontier Scientific, Logan, UT; TCI America, Portland , or; CombI - Blocks, San Diego, CA; Matrix Scientific, Columbia, SC; Acros, Morris Plains, NJ; Alfa Aesar, Ward Hill, MA; Apollo Scientific, UK; etc.) or can be synthesized by procedures known in technical.

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When a general or exemplary synthetic procedure is concerned, someone skilled in the art can easily determine the appropriate reagents, if not indicated, to extrapolate from general or exemplary procedures.

[000223] In general procedures 1 to 43 described here, although some of the procedures are generalized and exemplary, the time spent is used to indicate that these general procedures were the procedures used to synthesize the compounds. Some of the general procedures are used as examples to prepare specific compounds. Someone skilled in the art can easily adapt such procedures to the synthesis of other compounds. It should be understood that the R groups shown in the general procedures are understood to be generic and non-limiting, and do not correspond to the definitions of R groups elsewhere in this document. Each such group R represents one or multiple chemical moieties which may be the same or different from other chemical moieties also represented by the same symbol R. Furthermore, the representation of an unsubstituted position in structures shown or referred to in the general procedures is for convenience and it does not prevent substitutions as described elsewhere here. For specific groups that may be present, either as R groups in the general procedures or as opcionasis substituents not shown, refer to the descriptions in the remainder of this document, including the claims, summary and detailed description. It should also be understood that the compound numbers shown in the general schemes and general procedures in the Examples are for convenient reference only, and do not correspond to the numbers used elsewhere throughout this document. For example, the nitropyridine compound (1) in general scheme I is different from the compound of formula 1

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113/470 r '

Descritos · described here.

General Scheme I for the Synthesis of 5-Aryl-3- (Substituted-Benzyloxy) Pyridin-2-ylamine (6):

General Scheme II for the Synthesis of 5-Aryl-3- (Substituted-Benzyloxy) Pyrazin-2-ylamine

General Procedure 1 [000224] For the Synthesis of 5-Bromo-3- (Substituted-Benzyloxy) Pyridin-2-ylamine (5): 1. Preparation of3- (substituted-benzyloxy) - 2-nitropyridine (3): To a stirred solution of Cs2CO3 (1.0 molar equivalent)) in DMF (0.2 M) under an atmosphere of N2 containing 3-hydroxy - 4- nitropyridine (Aldrich, 1.0 molar equivalent) was substituted benzyl bromide (1.0 molar equivalent). The mixture was stirred for 6 hours at room temperature. The reaction was then diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc two

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114/470 times. The organic layers were then combined, washed with H2O and brine, dried over Na2SÜ4, filtered, and concentrated to dryness in vacuo to yield 3- (substituted-benzyloxy) - 2-nitropyridine (3) as a solid.

2. Preparation of 3- (substituted-benzyloxy) -pyridin-2-ylamine (4): To a stirred mixture of AcOH and EtOH (1.3: 1) was suspended 3 (substituted-benzyloxy - 2-nitro-pyridine ( 1.0 molar equivalent, 1 M) and iron chips (1.0 molar equivalent). The reaction was heated slowly to reflux and allowed to stir for 1 hour. The reaction was cooled to room temperature, then filtered through a celite pad. The resulting filtrate was neutralized with concentrated NH4OH, and then extracted with EtOAc three times. The combined organic extracts were washed with saturated NaHCO3, H2O, and brine, dried over Na2SO4, filtered and concentrated to dryness under vacuum to produce 3- (substituted-benzyloxy) pyridin-2-ylamine (4) as a solid.

3. Preparation of 5-bromo-3- (substituted benzyloxy) -pyridin-

2-ylamine (5): A stirring solution of 3- (substituted-benzyloxy) pyridin-2-ylamine (4) (1.0 molar equivalent) in acetonitrile was cooled to 0 ° C using an ice bath. To this solution was added N-bromosuccinimide (Aldrich, 1.0 molar equivalent) in portions. The reaction was stirred at 0 ° C for 15 minutes. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc and partitioned with H2O. The organic was then washed with saturated NaHCO3 twice and brine once. Activated charcoal was added to the organic layer and heated to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum to one third of the original volume. The solids were then filtered to produce 5-bromo-3- (substituted benzyloxy)

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115/470 pyridin-2-ylamine (5) as a solid.

General Procedure 2 [000225] For the Synthesis of 5-Bromo-3- (Substituted-Benzyloxy) Pyrazin-2-ylamine.

Bi

Br

NH.

ΌΗ

Reflux

Br

NaH / THF [000226] To an ice-cooled solution of substituted benzyl alcohol (1.0 molar equivalent) and anhydrous tetrahydrofuran (0.14 M) was added sodium hydride (1.0 molar equivalent) slowly under an atmosphere of nitrogen. After stirring for 30 minutes, 3,5dibromopyrazin-2-ylamine (1.0 molar equivalent) in tetrahydrofuran (0.56 M) was added via an addition funnel at a rapid drop rate. As soon as the addition was completed, the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reverse phase HPLC. After 18 hours HPLC showed that most of the starting 3,5-dibromopyrazin-2-ylamine was consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified using silica gel eluting with 1: 1 ethyl acetate / dichloromethane to produce 5-bromo-3- (substituted-benzyloxy) -pyrazin-2-ylamine as a white solid in 60 to 90% production .

General Procedure 3 [000227] For the Synthesis of 5-Aryl-3- (Substituted-Benzyloxy) -Pyridin-2ylamine and 5-Aryl-3- (Substituted-Benzyloxy) -Pyrazin-2-ylamine.

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Arila

Br Pd (PPh ₃ ), CI, _y X DME / ΝεΧΌ, / Η, Ο, ⁶⁰ ° ^c '......... *' .-, lb J ph Aryl boronic acid r ' ^: R

Y: CH or N [000228] A mixture of 5-bromo-3- (substituted-benzyloxy) -pyridin-2ylamine or 5-bromo-3- (substituted-benzyloxy) -pyrazin-2-ylamine (1 molar equivalent) , aryl or ester boronic acid (1.2 molar equivalent), bis (triphenylphosphine) palladium II chloride (0.03 molar equivalent) and sodium carbonate (3.0 molar equivalent) in ethylene dimethyl ether glycol and water (10: 0.5, 0.03 M) was degassed and charged with nitrogen three times, and then heated to reflux under nitrogen overnight. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica gel column to produce 5-aryl-3- (substituted-benzyloxy) -pyridin-2-ylamine, or 5-aryl-3- (substituted -benzyloxy) -pyrazin-2-ylamine.

General Procedure 4 [000229] For Amidation Reaction of 6-amino-5 (substituted-benzyloxy) -pyridin-3-yl] -benzoic acid:

[000230] To a solution of 6-amino-5- (substituted-benzyloxy) pyridin-3-yl] -benzoic acid (1 molar equivalent), 1 hydroxybenzotriazole hydrate (HOBT, 1.2 molar equivalent), and hydrochloride

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC, 1.2 molar equivalent) in DMF (0.2 M) amine (1.2 molar equivalent) was added. The reaction solution was stirred at room temperature during the night

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117/470 t, then diluted with EtOAc, and partitioned with H2O. The organic was separated and the aqueous was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness in vacuo. The material was purified using column chromatography (silica gel, 99: 1 to 95: 5 CH2Cb / MeOH). The product-containing fractions were concentrated in vacuo to produce the amine product.

General Procedure 5 [000231] For the preparation of 3- (substituted-benzyloxy) - 5- (3dalkylaminaminyl-1 H-indol-5-yl) -pyridin-2-ylamine:

R [000232] To a solution of benzotriazole (1.0 molar equivalent) in dichloromethane (0.2 M) was added amine (1.0 molar equivalents). The reaction was stirred for 5 minutes at room temperature after which formaldehyde (37% by weight, 1.0 molar equivalent) was added and the reaction was buffered and stirred at room temperature for 3 hours. Since TLC (10% ethyl acetate: dichloromethane) showed the consumption of starting benzotriazole, the reaction was dried with anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo. The crude product was purified with a silica gel column eluting with 1: 1 ethyl acetate: dichloromethane to produce the desired product as a white solid.

[000233] To a solution of the aminomethylbenzotriazole intermediate (1.0 molar equivalent) in dichloromethane (0.43 M) was added

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118/470 aluminum chloride (2.0 molar equivalent), and then followed by 3- (2,6-Dichloro-benzyloxy) - 5- (1 H-indol-5-yl) -pyridine-2-ylamine (1.1 molar equivalent). The reaction was buffered and heated with stirring to 40 ° C for 3 to 4 hours. The reaction was then removed from heating and allowed to cool to room temperature. The reaction mixture was diluted with sodium hydroxide (0.2 M) and chloroform, retamped and vigorously stirred at room temperature to dissolve the residue in the flask. Chloroform was extracted from the aqueous, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified with a silica gel column, first eluting with 1: 1, ethyl acetate: dichloromethane, to elute less polar impurities and then eluting the product with 90: 9: 1, chloroform: methanol: hydroxide ammonium. (Produces 10 to 67%.) General Procedure 6 [000234] For the Synthesis of 3- (Substitited-benzyloxy) - 5-phenyl-pyridin-2-amine using example I - 88:

[000235] To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example 1 - 87, 3.27 g, 11.8 mmoles) in methanol (30 ml) was added Pd (OH) 2 ( 2.5 g, 2.37 mmoles). The mixture was degassed and charged with hydrogen three times, and then stirred under a

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119/470 hydrogen test for 5 hours. The reaction was filtered through a pad of celite, washed with methanol, and condensed. After high vacuum, dry 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04 g, 93% yield). MS m / z 187 [M + 1].

[000236] To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g, 10.95 mmol) in THF (anhydrous, 30 mL) was added NaH (1.31 g, 32, 85 mmoles) slowly. The mixture was stirred under nitrogen for 20 minutes, and then trityl chloride (3.66 g, 13.14 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over Na2SO4. After filtering and condensing, the crude product was purified on a silica gel column eluting with EtOAc - Hexane (1: 10) to provide 5-phenyl-

2- (trityl-amino) -pyridin-3-ol (1.09 g, 23% yield). MS m / z 427 [M + 1].

[000237] To a solution of 5-phenyl- 2- (trityl-amino) -pyridin-3-ol (100 mg, 0.24 mmol) in THF (3 mL) was added Cs2CO3 (79 mg, 0.24 mmol ). The mixture was stirred at room temperature for 20 minutes, and then 3-methoxybenzylbromide (0.037 ml, 0.26 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane (5 ml), and filtered to remove the salts. The solvents were evaporated, and the residue was dissolved in 10% trifluoroacetic acid in dichloromethane (2 ml). The reaction was stirred for 2 hours, and evaporated. The residue was dissolved in dichloromethane, washed with saturated NaHCO3, and dried over Na2SO4. After filtration and concentration, the crude product was purified on a silica gel column eluting with methanol-dichloromethane (from 3% to 15% gradient) to provide 3- (3-methoxy-benzyloxy) -6-phenyl- pyridine-

2-ylamine as a white solid (43.5 mg, 60% yield). General procedure 7

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120/470 [000238] For the synthesis of 3- (benzyloxy-substituted) - 5-aryl-pyridin-2-amine using Example 1 - 106:

NO, [000239] To a solution of 2-amino- 5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] pyridin-3-ol (prepared according to the procedures for 2-amino-

5-phenyl-pyridin-3-ol in Example 1 - 88) (45.5 mg, 0.14 mmol) in DMF (3 mL) at 0 ° C NaH (50% in oil) (5.6 mg) was added , 0.14 mmol) and the mixture was stirred at 0 ° C for 20 minutes. Then 1Bromomethyl-3-nitro-benzene was added and the mixture was stirred at 0 ° C for 1 hour and at room temperature for 2 hours. Cold 1N aqueous HCl (0.1 ml) was added and the solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (CH2Cl2: MeOH: NH4OH = 100: 3: 0.3) to provide 5- [4- (2morpholin-4-yl-ethoxy) -phenyl] -3- (3-nitro -benzyloxy) -pyridin-2-ylamine as a yellow solid (44 mg, 68%).

General procedure 8 [000240] For the synthesis of {4- [6-Amino-5- (benzyloxy - substituted) pyridin-3-yl] -phenyl} - [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-il} -methanone using Example 1 - 111:

N

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1. 6-Amino-5-benzyloxy - nicotinic acid was prepared according to procedure 3 of 3-benzyloxy - 5-bromo-pyridin-2ylamine and 4- (4,4,5,5-tetramethyl- [1 , 3.2] dioxaborolan-2-yl) -benzoic. MS m / z 321 (M + 1).

2. [4- (6-amino-5-benzyloxy - pyridin-3-yl) -phenyl] - [(2R) - 2pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone was prepared following procedure 4 using 6-amino-5-benzyloxy-nicotinic acid and (2R) -pyrrolidin-1-ylmethyl-pyrrolidine (prepared in Example 1 - 39). MS m / z 457 (M + 1).

3. To a solution of [4- (6-amino-5-benzyloxy - pyridin-3-yl) phenyl] - [(2R) -pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone (2.28 g, 5.00 mmoles) in methanol (25 ml) 10% Pd / C (100 mg) was added. The mixture was degassed and charged with hydrogen three times, and then stirred under a hydrogen test flask overnight. The reaction was filtered through a pad of celite, washed with methanol, and condensed. After high vacuum, dry [4- (6-amino-5-hydroxypyridin-3-yl) -phenyl] - [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -methanone was obtained (1 , 74 g, 95% yield). ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1 H), 7.54 (m, 3 H), 7.46 (m, 2 H), 7.14 (s, 1 H ), 5.68 (s, 2 H), 4.22 (m, 1 H), 3.45 (m, 2 H), 2.66 (m, 1 H), 2.52 (m, 4 H ), 1.96 (m, 2 H),

1.84 (m, 3 H), 1.64 (m, 4 H): MS m / z 367 (M + 1).

4. To a stirred solution of [4- (6-amino-5-hydroxy - pyridin-

3-yl) -phenyl] - [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone (100 mg, 0.27 mmol) in anhydrous DMF (15 mL) under an N2 atmosphere con

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122/470 having, at 0 ° C, sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol) was added. The mixture was allowed to stir at 0 ° C for 30 minutes. 1- (Bromomethyl) -4-fluoro- 2- (trifluoromethyl) benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2 x 25 ml). The organic layers were combined, washed with H2O (1 x 15 ml), brine (1 x 15 ml), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to produce {4- [6 amino-5- (4-fluoro-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) - 2pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone as non-entirely white crystals.

General procedure 9 [000241] For the synthesis of [6-amino-5- (benzyloxy - substituted) -pyridin-3yl] -phenyl-amide of 2-Dialkylamino-ethanesulfonic acid using Example 1 - 243.

F

1. To a solution of 4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-

2-yl) -phenylamine (5 g, 22.8 mmoles) in dichloromethane (120 ml) N-methyl morpholine (7.5 ml, 68.4 mmoles) was added. This mixture was cooled to 0 ° C under a nitrogen atmosphere. Chloride 2

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123/470 chloroethanesulfonyl (2.5 ml, 23.9 mmoles) in dichloromethane (60 ml) was then added in drops with stirring. As soon as the addition was complete, the flask was shaken at 0 ° C for 1 hour and then at room temperature while monitoring by TLC (1: 1 ethyl acetate: hexanes) and staining with ninhydrin. After 4 hours of stirring, some starting boronic ester remained and an additional 0.2 equivalents (0.5 mL) of 2-chloroethanesulfonyl chloride in dichloromethane (25 mL) was added in drops at room temperature. After 1 hour the boronic ester was consumed as shown by TLC and the total reaction volume was reduced by half by means of rotary evaporation. The contents were diluted with ethyl acetate (200 ml), washed with 50% brine (2 x 100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel (120 g) and eluting with 10% ethyl acetate, dichloromethane to produce [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- 2yl) -phenyl] -amide of ethylene sulfonic acid as a white solid (6.2 g, 20.2 mmoles, 89% yield). ^{1 H} NMR (CDCb, 300 MHz), δ 7.76 (d, J = 8.4, 2 H), 7.12 (d, J = 8.45, 2 H), 6.65 (s, 1 H), 6.55 (dd, J = 9.77, 6.7, 1 H), 6.31 (d, J = 16.54, 1 H), 5.96 (d, J = 9.8 , 1 H), 1.33 (s, 12 H).

2. To a solution of [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-

Ethylene sulfonic acid 2-yl) -phenyl] -amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0 mmol) in methanol (5 mL), and the reaction was stirred at room temperature and monitored by TLC (1: 1 ethyl acetate: hexanes). After 2 hours the reaction was concentrated in vacuo and the residue divided between ethyl acetate (50 ml) and water (50 ml). The ethyl acetate was then washed with 50% brine (1 x 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using a 10 g pre-packaged silica gel column, eluting with 1: 1 ethyl acetate: dichloromethane to provide [4- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl)

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124/470 2-diethylamino-ethanesulfonic acid phenyl] -amide as a white solid (0.346 g, 0.90 mmol, 56%). ^{1 H} NMR (CDCb, 300 MHz) δ 7.78 (d, J = 6.65, 2 H), 7.15 (d, J = 6.66, 2 H), 3.20 (m, 2 H ), 3.0 (m, 2 H), 2.55 (q, J = 7.15, 7.16, 4 H), 1.34 (s, 12 H), 1.05 (t, J = 7.19, 6 H).

3. 2-Diethylamino-ethanesulfonic acid {4- [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} -amide was prepared following procedure 3 Suzuki coupling system of 5-bromo-3 (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-ylamine and [4- (4,4,5,5-tetramethyl- [1,3,2 ] dioxaborolan-2-yl) -phenyl] -amide of 2-diethylaminoethanesulfonic acid prepared in part 2 as a white solid at 60% production.

General procedure 10:

1: 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl) aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reaction was stirred for 13 hours where the TLC analysis showed the consumption of all starting materials. The solution was washed with saturated NaHCO3 (3 x 50 ml), water (3 x 50 ml) and brine (3 x 50 ml). The organic layer was dried over Na2SO4 and the solvent removed to produce a white crystalline solid [4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl ester - phenyl] -carbamic,

4.45 g, 91%. ^{1 H} NMR (CDCh 300 MHz) δ 1.4 (s, 12 H), 7.1 (brs, 1 H), 7.3 (d, 2 H), 7.5 (d, 2 H), 7 , 8 (d, 2 H), 8.3 (d, 2 H).

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2: [4- (4,4,5,5-T etramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -carbamic acid phenyl ester (500 mg, 1.3 mmol) was dissolved in anhydrous dichloromethane (0.5 ml) and triethylamine (0.187 ml,

1.3 mmol). To this stirred solution was added 1-methyl piperazine (or any other amine) (0.144 ml, 1.3 mmol). The solution turned yellow immediately, and TLC analysis showed the consumption of all starting materials. The reaction was washed with water (3 x 500 ml), saturated sodium bicarbonate (2 x 200 ml) and dried before removing the solvents in vacuo. Boronic esters were used without purification.

3: To a mixture of 2.1 ml of DME and 2.8 ml of Na2CO3 at

2N 100 mg of bromide scaffolding, 1 equivalent of boronic acid, and 5 mol% of Pd (PPh3) 4 were added. The reaction was stirred and heated to 80 ° C overnight in a two drachma vial. The crude mixture was filtered through ceolite and extracted with EtOAc (2 x 100 ml). The combined extracts were washed with NaHCO3 (1 x 100 ml), followed by water (1 x 100 ml), and then saturated brine (1 x 100 ml). The resulting mixture was concentrated in vacuo. The residue was dissolved in hexane and purified by means of column chromatography.

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General procedure 11:

F

1: To a solution of 3- [1- (2,6-Dichloro-3-fluoro-phenyl) -ethoxy] pyridin-2-ylamine (10.0 g, 33.2 mmoles) in acetonitrile (600 mL) and acetic acid (120 ml) was added N-iodosuccinimide (11.2 g, 49.8 mmoles). The mixture was stirred at room temperature for 4 hours and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, dried over Na2SO4. The crude product was purified on a silica gel column to provide 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - 5-iodo-pyridin-2ylamine (7.1 g, 50% of production). MS m / z 427 (M + 1).

2: To a solution of 3- [1- (2,6-Dichloro-3-fluoro-phenyl) -ethoxy] - 5iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and tert ester -butyl of prop-2-ynyl-carbamic acid (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N (60 mL) was added Cul (63 mg, 0.3 mmol) and Pd (PPh3 ) 4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was completed. The mixture was extracted with EtOAc and washed with water. The crude product was purified on a silica gel column eluting with 20 - 40% EtOAc in hexanes to provide acid tert-butyl ester (3- {6-Amino-5- [1- (2,6-dichloro-3 -fluor-phenyl) -ethoxy]

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127/470 pyridin-3-yl} -prop-2-ynyl) -carbamic (2.2 g, 29% yield).

3: The acid solution (3- {6-Amino-5 [1- (2,6-dichloro-3-fluor-phenyl) -ethoxy] -pyridin-3-yl} -prop- 2-ynyl) -carbamic in 25% TFA in dichloromethane was stirred for 2 hours, then washed with 2N NaOH, water twice, brine, dried over Na2SO4. After filtration and evaporation, 5- (3-amino-prop-1-ynyl) -3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine was obtained in 93 % of production.

4: To a solution of 5- (3-amino-prop-1-ynyl) -3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine (0.282 mmol, 1 equivalent) and 4-nitrophenyl chloroformate (1 equivalent) in anhydrous dichloromethane (10 ml) was added pyridine (1 equivalent). The reaction was stirred for 4 hours under nitrogen, and then the selected amine (1 equivalent) and triethylamine (1 equivalent) were added. The mixture was refluxed for 5 minutes and cooled to room temperature. The reaction mixture was washed with water. The organic layer was evaporated and purified on a silica gel column eluting with 20% methanol in dichloromethane on prepackaged silica columns. Final yields varied between 24% and 71%. General procedure 12:

1: To a solution of 5- (3-amino-prop-1-ynyl) -3- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2-ylamine (prepared in procedure 11 ) (400 mg, 1.1 mmol) in dichloromethane (17 mL) chloroacetyl chloride (153 mg, 1.4 mmol) was added. The reaction was stirred at room temperature with a TLC monitor at the completion of the reaction.

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Upon completion, the solvent was evaporated to obtain the crude product.

2: To a solution of N- (3- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -prop-2-inyl) - 2-chloro-acetamide (1 equivalent) in acetonitrile (5 equivalent) was added to the individual amine (5 equivalent). The mixture was refluxed under nitrogen overnight. After evaporation of the solvent, the residue was purified on a silica gel column eluting with 1 - 10% methanol in dichloromethane to provide the product with yields ranging from 47% to 97%. General procedure 13:

1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0 ° C was added Nbromosuccinimide (37.1 g, 0.21 mol) for 30 minutes. The mixture was stirred for 0.5 hour, after which the reaction was then diluted with EtOAc (900 ml) and partitioned with H2O (900 ml). The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness in vacuo to provide 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%) . ^{1 2 H} NMR (CDCh, 300 MHz) δ 4.63 - 4.78 (brs, 2 H), 5.04 (s, 2 H), 7.07 (d, 1 H, J, 1.8 Hz ), 7.33 - 7.42 (m, 5 H), 7.73 (d, 1 H, J, 1.8 Hz).

2. To a stirred mixture of 3-benzyloxy-5-bromo-pyridin-2ylamine (31.0 g, 0.11 mol) in a mixture of DME (600 ml) and H2O (600 ml) was added 4-carboxymethylboronic acid (29.9 g, 0.11 mol),

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Pd (PPh3> 4 (6.4 g, 5.55 mmoles), and Na2CO3 (82.0 g, 0.78 mol). The reaction was slowly heated to reflux and allowed to stir for 3 hours. The reaction was cooled to at room temperature, then diluted with CH2Cl2 (1.5 L) and partitioned with H2O (700 mL) The organic layer was washed with saturated NaHCO3 (700 mL), dried (Na2SO4), filtered, and concentrated in vacuo. crude was purified by column chromatography (silica gel, 1: 1 to 4: 1 EtOAc: hexanes) and the product-containing fractions were combined and concentrated in vacuo to provide 4- (6-amino-5-) acid methyl ester benzyloxy pyridin-3-yl) -benzoic acid (29.4 g, 0.086 mol, 79%). ^{1 H} NMR (CDCl3 300 MHz) δ 3.92 (s, 3 H), 4.82 - 4.94 (brs , 2 H), 5.15 (s, 2 H), 7.22 (d, 1 H, J, 1.8 Hz), 7.33 - 7.42 (m, 5 H), 7.64 ( d, 2 H, J, 8.6), 7.98 (d, 1 H, J, 1.8 Hz), 8.06 (d, 2 H, J, 8.6 Hz).

3. To a stirred solution of 4- (6 amino-5-benzyloxy - pyridin-3-yl) -benzoic acid methyl ester (10.0 g, 0.03 mol) in EtOH: H2O (95.5, 600 mL) Pd / C (15.9 g, 0.015 mol) was added (the reaction was degassed under vacuum). The solution was allowed to stir under an atmosphere of H2 for 22 hours. The solution was filtered through wet celite and the celite washed with EtOH. The filtrate was concentrated in vacuo to produce 4- (6-Amino-5-hydroxypyridin-3-yl) -benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). ^{1 H} NMR (MeOD, 300 MHz) δ 3.90 (s, 3 H), 7.21 (d, 1 H, J, 1.9 Hz), 7.62 (d, 2 H, J, 8, 5 Hz),

7.76 (d, 1 H, J, 1.9 Hz), 8.04 (d, 2 H, J, 8.5 Hz).

4. To a stirred solution of 4- (6 amino-5-hydroxy-pyridin-3-yl) -benzoic acid methyl ester (2.3 g, 9.3 mmoles) in CH2Cl2 (180 mL) was added N, N-diisopropylethylamine (3.2 ml, 0.019 mol), 4-methyl-benzenesulfonyl chloride (2.66 g, 0.014 mol), and PS-DMAP (typical amount). The reaction was stirred at room temperature for 6 hours then filtered to remove the resin. The resin was washed with CH2Cl2 (3 x 20 mL), and the combined fractions were washed

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130/470 with 10% citric acid (100 ml), saturated NaCl (100 ml), dried (Na2SÜ4) and filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel, 95% CH2Cl2 95: 5 CH2Cl2: MeOH) and the fractions containing the desired product were combined and concentrated in vacuo to produce 4- [6] methyl methyl ester. -Amino- 5- (toluene-4-sulfonyloxy) -pyridin-3yl] -benzoic acid (3.3 g, 8.2 mmol, 88%). ^{1 H} NMR (CDCb, 300 MHz) δ 2.47 (s, 3 H), 3.93 (s, 3 H), 4.81 - 4.88 (brs, 2 H), 7.36 - 7, 44 (m, 5 H), 7.81 (d, 2 H, J, 8.3 Hz), 8.05 (d, 2 H, J, 8.4 Hz), 8.19 - 8.27 ( brs, 1 H).

5. To a stirred solution of 1- (3-fluorine-2-trifluoromethylphenyl) -ethanol (2.0 g, 9.6 mmoles) in anhydrous DMF (500 mL) at 0 ° C under an N2 atmosphere was added NaH (0.38 g, 9.6 mmoles). The reaction was allowed to stir for 0.5 hour. A solution of 4- [6-Amino-5- (toluene-4-sulfonyloxy) -pyridin-3-yl] benzoic acid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL ) was added to the reaction mixture which was allowed to reach room temperature slowly and stirred for 21 hours at this temperature. The reaction was diluted with EtOAc (500 ml) and H2O (100 ml). The organic layer was separated and the aqueous one was also extracted with EtOAc (1 x 200 ml). The organic layers were combined and washed with brine (1 x 100 ml), dried with Na2SO4 and concentrated to dryness in vacuo. The crude mixture was purified by column chromatography (silica gel, 40: 60 to 70: 30 EtOAc: hexanes) and the product-containing fractions were combined and concentrated in vacuo to produce 4- {6-amino- 5- [1- (3-fluoro-2trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid (1.4 g, 3.2 mmoles, 34%). ^{1 H} NMR (CDCb, 300 MHz) δ 1.73 (d, 3 H, J, 6.2 Hz), 3.91 (s, 3 H), 4.87 - 4.64 (brs, 2 H) , 5.81 (q, 1 H, J, 6.1, 6.3 Hz), 6.92 (d, 1 H, J,

1.8 Hz), 7.38 (d, 2 H, J, 8.5 Hz), 7.46 - 7.66 (m, 3 H), 7.93 (d, 1 H, J,

1.8 Hz), 8.02 (d, 2 H, J, 8.5 Hz).

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6. To a stirred solution of 4- {6 amino- 5- [1- (3-fluoro-2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid methyl ester (1.4 g , 3.2 mmoles) in hot IPA (72 ml) H2O (38 ml) containing LiOH (0.68 g, 16.2 mmoles) was added. The reaction was heated to reflux for 3.5 hours. The reaction was neutralized and diluted with EtOAc (200 ml) and extracted under cooling. The organic layer was washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to produce 4- {6-Amino-5- [1- (3-fluoro-2-trifluoromethyl-phenyl) -ethoxy] pyridin- 3-yl} -benzoic acid (1.2 g, 2.8 mmol, 88%). ¹ H NMR (MeOD, 300 MHz) δ 1.75 (d, 3 H, J, 6.2 Hz), 4.88 - 4.93 (m, 1 H), 7.01 (d, 1 H, J, 1.8 Hz), 7.39 (d, 2 H, J, 8.3 Hz), 7.52 - 7.67 (m, 3 H), 7.80 (d, 1 H, J, 1.8 Hz), 7.97 (d, 2 H, J, 8.3 Hz).

7. Preparation of amide compounds: A stirred solution of 4- {6-Amino- 5- [1- (3-fluoro-2-trifluoromethyl-phenyl) -ethoxy] - pyridin-3-yl} -benzoic acid (50 mg, 0.12 mmol), EDC (27.0 mg, 0.13 mmol) and HOBt (18.0 mg, 0.13 mmol) in DMF (2 mL) was added to a two-drachma vial containing NHR1R2 ( 0.12 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with CH2Cl2 (3 mL) and partitioned with H2O. The organic was washed separately with saturated NaCl (1 x 2 ml) and saturated NaHCO3 (1 x 2 ml). The organic was concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99: 1 to 95: 5 CH2Cl2 / MeOH). The product containing fractions were concentrated in vacuo to produce the amide compounds.

General procedure 14:

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1: To a mixture of 1- (2-chloroethyl) pyrrolidine hydrochloride (200 mg, 1.18 mmol) and 4- [4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan - 2yl) -phenyl] -1 H-pyrazole (229 mg, 1.19 mmol) in DMF (6 mL) was added Cs2CO3. The mixture was stirred at room temperature overnight. Water (10 ml) was then added to the mixture. The product was extracted with EtOAc (3 x 10 ml). The combined extracts were then washed with brine (5 x 10 ml) to remove DMF, then dried over Na2SO4, and concentrated (142 mg, 41% yield).

2: To a mixture of 3- [1- (2,6-Dichloro-3-fluoro-phenyl) -ethoxy] - 5iodo-pyridin-2-ylamine (200 mg, 0.468 mmol), pinacol boronic ester (1, 2 equivalent), Na2CO3 (149 mg, 1.41 mmol) in water (1.25 mL), and dimethyl ethyl glycol (3.75 mL, 0.1M) Pd (PPh3) 2Cl2 (16 mg, 0.020 mmol) was added ) in a microwave reaction vessel. The system was degassed and charged with nitrogen. The mixture was stirred at 160 ° C in a microwave for 15 minutes. The mixture was cooled to room temperature followed by the addition of water (10 ml). The product was extracted with EtOAc (3 x 20 ml), dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC with 0.1% TFA in water and acetonitrile.

General procedure 15:

1: To a solution of 3 H-oxazolo [4,5-b] pyridin-2-one (13.6 g, 100 mmoles) in acetonitrile (600 ml) and acetic acid (120 ml) was added N-bromosucinimide ( 21.4 g, 120 mmoles). The mixture was stirred at room temperature for 4 hours and the reaction was quenched with Na2S2O5 solution. After evaporation, NaOH solution,

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133/470 brine, and dried over Na2SÜ4. The crude product was purified on a silica gel column to provide 6-bromo-3 H-oxazolo [4.5b] pyridin-2-one (11.5 g, 55% yield).

2: 6-Bromo-3 H-oxazolo [4,5-b] pyridin-2-one (21.5 g, 100 mmol) was suspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH -7. A lot of CO2 was released and the precipitate was also observed. The product was filtered, washed with water, and dried under high vacuum to provide 2-amino-5-bromo-pyridin-3-ol as a non-white solid (17.8 g, 98% yield).

3: To a solution of 2-amino-5-bromo-pyridin-3-ol (358 mg, 1.89 mmol) in DMF (8 mL) was added Cs2CO3 (620 mg, 1.89 mmol). The mixture was stirred at room temperature under nitrogen for 1 hour. To the reaction mixture added bromine compound (0.9 equivalent) in DMF (5 mL) slowly. The reaction solution was stirred under nitrogen for five hours, and then divided between water and ethyl acetate. The organic layer was washed with brine three times, dried over MgSO4. The crude product was purified on a silica gel column eluting with hexane - ethyl acetate (4: 1) to provide the product with 70% - 80% production. General procedure 16 using Example 1 - 488:

1. To a solution of 3-benzyloxy-5-bromo-pyridin-2-ylamine (1 g, 3.58 mmol) in dimethyl sulfoxide (7 mL) was added sequentially bis (pinacolate) diborane (1.0 g, 3, 94 mmoles), potassium acetate (1.05 g, 10.7 mmoles) [1,1'-bis (diphenylphosphino) ferrocine] dichloropalladium (II), complex with dichloromethane (1: 1) (146 mg, 0.18 mmol). The mixture was

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134/470 heated to 80 ° C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was washed with water (2 x 50 ml) and dried over magnesium sulfate. Concentration in vacuo produced crude boronate as a brown solid (1.13 g, 97%). ^{1 H} NMR (CDCh) δ 1.32 (s, 12 H), 5.08 (s, 2 H), 5.44 (brs, 2 H), 7.33 - 7.42 (m, 6 H) , 8.03 (s, 1 H).

2. An 18 mL reaction vessel was loaded with raw 3benzyloxy-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2ylamine (161 mg, 0 , 49 mmol), dimethoxyethane (3 mL) and 2bromopyridine (117 mg, 0.74 mmol). To this solution was added [1,1'bis (diphenylphosphino) ferrocin] dichloropalladium (II), complex with dichloromethane (1: 1) (20 mg, 0.05 mmol) and a 2M solution of cesium carbonate in water ( 0.75 mL, 1.5 mmol). The reactor was heated to 80 ° C for 66 hours under an atmosphere of nitrogen, then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml). The organic layer was washed with additional water (5 ml) and diluted with dimethylformamide (5 ml). Polymer-bound sulfuric acid (0.5 g, 2.1 mmol) was added to the organic solution, and the resulting mixture was gently stirred for 2 hours. The resin was filtered and washed with dimethylformamide, methanol and methylene chloride (3 x 5 ml of each solvent). Then the polymer was reacted with 2M ammonia in methanol for 1 hour. The resin was filtered and washed with additional 2M ammonia in methanol (2 x 5 ml), and the combined filtrates were concentrated in vacuo. Purification of the crude product by flash column chromatography produced 52.2 mg of product as a tan solid (38% yield).

General procedure 17:

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1. To the solution of 3- (2-Chloro-3,6-difluoro-benzyloxy) - 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin- 2-ylamine (procedure 16) (10.0 g, 24.3 mmoles) in t-butyl alcohol (50 ml) was added boc anhydride (5.83 g, 26.7 mmoles) and the reaction stirred at room temperature during the night. Additional boc anhydride (2.25 g, 10.3 mmoles) was added and the reaction stirred overnight again. The material was concentrated to a viscous black oil and used as is.

2. The raw boronic ester (theoretical 24.3 mmoles) in THF (150 ml) was added to a solution of sodium bicarbonate (16.3 g, 194 mmoles) in water (150 ml) and acetone (23 ml). The mixture was cooled to 2 ° C and oxone (13.5 g, 21.9 mmoles) was added slowly, keeping the temperature below 8 ° C. Near the completion of the addition, the reaction was stirred for 5 minutes then quenched with sodium bisulfite (14.2 g) in water (28 mL). Ethyl acetate was added (200 ml) and the layers separated. The aqueous layer was neutralized with 6N HCl and extracted with ethyl acetate (2 x 200 ml). The combined organics were washed with water (250 ml) and brine (250 ml), dried (Na ₂ SO4) and concentrated to a black crude oil. Chromatography on silica gel (ethyl acetate / hexane) gave the product as a light brown foam (4.78 g, 49.0%). ^{1 H}

NMR (CDCls) δ 1.48 (s, 9H), 1.74 (d, 3 H), 5.75 (q, 1 H), 6.61 (d, 1 H), 76.89 (dt, 1 H), 6.94 - 7.04 (m, 2 H), 7.26 (d, 1 H), 8.19 (bs, 1 H). MS m / z 401 (M + H) ⁺ .

3. To cesium carbonate in a 2-drachma jar, [3- (2-Chloro-3,6-difluoro-benzyloxy) -5-hydroxy-pyridin-2-yl] -carbamic acid tert-butyl ester (100 mg, 0.25 mmol) in anhydrous DMF (1 mL) followed by benzyl bromide (89.2 gL, 0.75

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136/470 mmol). The flask was capped and stirred at 90 ° C overnight. The reaction was filtered through a 5 ml Chem-Elut tube pre-moistened with water (3.5 ml) and eluted with 1: 1 ethyl acetate: methylene chloride. After partial concentration, 4N HCl in dioxane (1 - 2 mL) was added and the solution concentrated. Reverse phase chromatography (water: acetonitrile, 0.05% TFA) followed by lyophilization, provided the desired product as a non-white amorphous solid (25.3 mg, 20.0%) and the bis-addition product as a tan amorphous solid (35.2 mg, 23.7%).

General procedure 18:

[000242] Sodium borohydride (1.5 molar equivalent) was added to the ketone solution (3.89 mmol) in 10 mL of ethanol under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 12 hours. The mixture was then placed in an ice bath and quenched with diluted aqueous HCl. Ethanol was evaporated and EtOAc was added to extract the aqueous solution. The EtOAc layer was dried over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide an oil residue, compound A5. The residue was used without further purification.

[000243] 3-Hydroxyl - 2-nitropyridine (1.1 molar equivalent) and triphenylphosphine (1.5 molar equivalent) were added to a solution of compound A5 (1.1 mmol) in 10 ml of THF. The reaction mixture was then placed in an ice bath and diisopropyl azodicarboxylate (1.5 molar equivalent) was added. The ice bath was removed and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated to provide a yellow oil residue. The residue was purified by chromatography on silica gel (eluate

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137/470 (EtOAc in hexanes) to provide compound A1.

[000244] 2M HCl (0.2 ml) was added to the solution of compound A1 (0.97 mmol) in 2 ml of ethanol. The mixture was then placed in an ice bath and Fe powder (365 mg) was added slowly. The reaction was heated to 85 ° C for 1 hour and cooled to room temperature. Celite (0.5 g) was added to stir and the resulting mixture was filtered through a bed of celite and rinsed with ethanol. The filtrate was evaporated to provide a brown oil residue, compound A2. The residue was used without further purification.

[000245] Periodic acid (0.25 mol equivalent), iodine (0.5 mol equivalent), H2O (0.5 ml), and concentrated sulfuric acid (0.03 ml) were added to a solution of compound A2 in 3 mL of acetic acid. The reaction mixture was heated to 85 ° C for 5 hours. The reaction mixture was then cooled in an ice bath and basified with saturated aqueous Na2CO3 to a pH of 3 - 4. Ethyl acetate was added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a brown oil residue. The residue was purified by chromatography on silica gel (eluting with EtOAc and hexanes) to provide the desired product, compound A3.

General procedure 19:

A3

A4 [000246] Boronic ester or boronic acid (1.3 molar equivalent) was added to a solution of compound A3 (0.47 mmol) in 5 mL of DME. The mixture was purged with nitrogen several times and then dichlorobis (triphenylphosphine) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 1 mL of H2O was added to the reaction mixture and the resulting solution was heated to

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138/470 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a dark brown oil residue. The residue was purified by chromatography on silica gel (eluting with CH3OH, CH2CU EtOAc, and hexanes) to provide the desired product, compound A4.

General procedure 20:

R

[000247] Compound A6 was prepared using the general procedure 19. O- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium (HATU) phosphorus (1.1 equivalent molar), diisopropylethyl amine (5 molar equivalent) and amine (1.3 molar equivalent) were added to a solution of compound A6 (0.17 mmol) in 3 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. Saturated NaHCO3 was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a brown oil residue. The residue was purified by chromatography on silica gel (eluting with EtOAc and hexanes) to provide the desired amide product, compound A7, as a yellow oil.

General procedure 21:

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A7 ^A8 [000248] Acid (16 molar equivalent or less) was added to compound A7 (0.13 mmol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 ° C for 12 hours. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (eluting with CH3OH, EtOAc and CH2Cl2) to provide the desired amide product, compound A8, as a white to yellowish solid.

General procedure 22:

[000249] Compound A9 was prepared using the general procedure 19. DI dicarbonate - tert-butyl (3 molar equivalent) and

4- (dimethylamino) pyridine (0.14 molar equivalent) was added to a solution of compound A9 (3 mmol) in 20 mL of DMF. The reaction mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a residue of yellow brown oil. The residue was purified by chromatography on silica gel (eluting with 25 - 30% EtOAc in hexanes) to provide the desired product, compound A10 as a yellowish oil (87.8% yield). Ozone was bubbled

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140/470 through a solution of compound A10 in 50 ml of CH2 Cl2 at -78 ° C and dimethyl sulfide was added to quench the reaction. Saturated sodium chloride was added to the reaction mixture and EtOAc was added to extract the aqueous solution. Combined EtOAc layer was dried over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a yellow oil residue. The residue was purified by chromatography on silica gel (eluting with 35 - 40% EtOAc in hexanes) to provide the desired product, compound A11 as a yellowish oil (58.4% yield).

General procedure 23: Reductive amination

^A11 A12 A13 [000250] Amine hydrochloride salt (1.2 molar equivalent), sodium acetate (2 molar equivalent to the amine hydrochloride salt) were added to a solution of compound A11 (0.45 mmol) in 4 mL of CH3OH under a nitrogen atmosphere. Molecular sieve (0.5 g) was added to the reaction mixture and then sodium cyanoborohydride (2 molar equivalent) was added. The resulting mixture was stirred at room temperature for 12 hours under an atmosphere of nitrogen. The reaction mixture was filtered through a bed of celite and the filtrate was evaporated and purified by chromatography on silica gel (eluting with CH3OH, EtOAc, and CH2CL2) to provide the desired product, compound A12 as an oil (52.6% of production). Acid (16 molar equivalent or less) was added to compound A12 (0.17 mmol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 ° C for 12 hours. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (eluting with CH3OH, EtOAc and CH2Cl2) for

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141/470 to provide the desired product, compound A13.

General procedure 24:

A11 A14 A15 [000251] O-phenyldiamines (1.2 molar equivalent) and sodium bisulfite (2.1 molar equivalent) were added to a solution of compound A11 (0.41 mmol) in 5 ml of DMA. The resulting solution was heated to 110 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a residue of yellow brown oil. The residue was purified by chromatography on silica gel (eluting with EtOAc in hexanes) to provide the desired product, compound A14. 16 molar equivalent acid or less) was added to compound A14 (0.16 mmol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 ° C for 12 hours. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (eluting with CH3OH, EtOAc and CH2Cl2) to provide the desired amide product, compound A15. General procedure 25:

\ /

Boc ^ 'Boc

A17

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ο. , ο Β

Α18 [000252] Di-tert-butyl dicarbonate (3 molar equivalent), 4 (dimethylamino) pyridine (0.14 molar equivalent) were added to a solution of compound A3b (2 mmol) in 10 mL of DMF. The reaction mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a residue of yellow brown oil (compound a16). The residue was used without further purification.

[000253] Bis (pinacolate) diboro (1.2 molar equivalent) and potassium acetate (3.4 molar equivalent) were added to a solution of compound a16 in 4 ml of DMSO. The mixture was purged with nitrogen several times and then dichlorobis (triphenylphosphine) palladium (II) (0.05 molar equivalent) was added. The resulting solution was heated to 80 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a dark brown oil residue. The residue was purified by chromatography on silica gel (eluting with 30% EtOAc in hexanes) to provide the desired product, compound A17 (76% yield). HCl (5 molar equivalent) was added to a solution of compound A17 (0.43 mmol) in 4 ml of CH2Cl2. The resulting mixture was heated at 50 ° C for 12 hours. Saturated NaHCO3 was added to the reaction mixture to neutralize the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. O

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Na2SÜ4 was filtered and the filtrate was evaporated to provide the desired product (compound A18) as a yellow solid (75% yield).

General procedure 26:

A17 A19 A20 [000254] Compound A17 (1.3 molar equivalent) was added to a solution of aryl halide (0.36 mmol) in 3 mL of DME. The mixture was purged with nitrogen several times and then dichlorobis (triphenylphosphine) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 0.8 mL of H2O was added to the reaction mixture and the resulting solution was heated to 85 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a dark brown oil residue. The residue was purified by chromatography on silica gel (eluting with EtOAc in hexanes) to provide the desired product, compound A19 (74.4% yield). HCl (5 molar equivalent) was added to a solution of compound A19 (0.26 mmol) in 10 ml of isopropyl alcohol. The resulting mixture was heated at 50 ° C for 12 hours. The solvent was evaporated to provide the desired product, compound A20.

General procedure 27:

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A13. * 21 [000255] Compound A18 (1.3 molar equivalent) was added to a solution of aryl halide (0.21 mmol) in 3 mL of DME. The mixture was purged with nitrogen several times and then dichlorobis (triphenylphosphine) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 0.6 ml of H2O was added to the reaction mixture and the resulting solution was heated to 85 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a dark brown oil residue. The residue was purified by chromatography on silica gel (eluting with CH3OH, CH2CU EtOAc, and hexanes) to provide the desired product, compound A21.

General procedure 28:

A22

X = I, Br, Cl [000256] Amine (1.5 molar equivalent) and K2CO3 (1.5 molar equivalent) were added to a solution of 4-halobenzyl halide (1.0 molar equivalent) in 2 ml of toluene . The resulting mixture was treated with microwaves using a Smith synthesizer (150 ° C, 1 hour). Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution.

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Dry EtOAc layer over Na2SÜ4. The Na2SÜ4 was filtered and the filtrate was evaporated to provide the desired product, compound A23. The residue was used in procedure 11 without further purification to synthesize compound A22.

General procedure 29:

[000257] Amine (1.2 molar equivalent) and diisopropylamine (5 molar equivalent) were added to a solution of 4bromobenzenesulfonyl chloride (0.77 mmol) in 5 ml of CHCh under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide the desired product, compound A25. The residue was used in procedure 11 without further purification to synthesize compound A24.

General procedure 30:

A26 [000258] Boronic ester or boronic acid (1.2 molar equivalent) was added to a solution of 1-chloro-4-iodobenzene (0.84 mmol) in 10 mL of ethylene glycol dimethylether (DME) under an atmosphere of ni

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146/470 trogen. The mixture was purged with nitrogen several times and then dichlorobis (triphenylphosphine) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 1.8 ml of H2O was added to the reaction mixture and the resulting solution was heated to 85 ° C for 12 hours. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. Na2SO4 was filtered and the filtrate was evaporated to provide a dark brown oil residue. The residue was purified by chromatography on silica gel (eluting with CH3OH, CH2CU EtOAc, and hexanes) to provide the desired product, compound A27. Compound A27 was used in procedure 11 to synthesize compound A26.

General procedure 31 for chiral separation of Racematos [000259] The racemic sample was purified using preparative supercritical fluid chromatography SFC-MS. The purification conditions were: column - Chiralpak AD-H, 250 x 21 mm, 5 microns, column 100A (Column #: ADH0CJ - C1003); column temperature 35 ° C; mobile phase CO2 modified by 35% methanol (with 0.1% isopropylamine) - modified by CO2; preparative flow rate 52 mL / minute; isobaric pressure at 120 bar. The specific chirality of the isomers has not been definitively determined.

General procedure 32: using Example 1 - 617

in situ [000260] To a mixture of 4- [4- (6Amino-5-hydroxy - pyridin-3-yl) -benzoyl] - 2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg , 0.23 mmol) and 1- (1-bromo-ethyl) -3-trifluoromethyl

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147/470 benzene (64 mg, 0.25 mmol) in DMF (2 mL) NaH (12 mg, 0.47 mmol) was added at 0 ° C. The mixture was stirred overnight. LCMS showed that the reaction was complete, DMF and water were removed. TFA (2 ml) was added to the residue and stirred at room temperature for 3 hours. TFA was removed followed by the addition of methanol. The residue was purified by HPLC-prep. to provide (4- {6Amino-5- [1- (3-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (3,5-dimethylpiperazin-1-yl) -methanone (30 mg , 25.7% yield).

General procedure 33: using Example 1 - 616

in situ [000261] To a mixture of 4- [4- (6Amino-5-hydroxy - pyridin-3-yl) -benzoyl] - 2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg , 0.12 mmol) and 1- (1-bromo-ethyl) - 2-trifluoromethylbenzene (32 mg, 0.12 mmol) in DMF (2 mL) 2M Cs2CO3 (0.18 mL, 0.35 mmol) was added ), followed by water (0.5 ml), the mixture was stirred overnight then heated to 70 ° C for 8 hours, LCMS showed that the reaction was complete. DMF and water were removed. TFA (2 ml was added to the residue and stirred at room temperature for 3 hours. TFA was removed, followed by the addition of methanol. The residue was purified by HPLC-prep. To provide (4- {6 amino-5- [1- (2-trifluoromethyl-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) - (3,5-dimethylpiperazin-1-yl) -methanone (20 mg, 34.2% yield).

Procedure 34: using Example 1 - 624

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To a mixture of (2R, 6S) -4- [45-hydroxy-pyridin-3-yl) -benzoyl]-2,6-dimethyl-piperazine-1 [000262] (6-Aminocarboxylic acid) tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF (2 mL) 2M Cs2CÜ3 (0.35 mL, 0.7 mmol) was added followed by water (0.5 mL). The mixture was stirred at room temperature overnight LCMS showed that the reaction was complete, DMF was removed, followed by the addition of 4N HCl in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hours. Volatiles were removed followed by the addition of methanol. This solution was purified by HPLC-prep to provide {4- [6Amino-5- (2-methyl-benzyloxy) -pyridin-3-yl ] -phenyl} - (3,5-dimethyl-piperazin-1yl) -methanone (47 mg, 46.6% yield).

Procedure 35: using Example 1 - 635

a mixture of [3- (4-iodine [000263] A benzoyl) -3-aza-bicyclo [3,1,0] hex-5-yl] -carbamic acid tert-butyl ester (100 mg, 0.234 mmol )

3- [1- (2,5-dichloro-3-fluoro-phenyl) -ethoxy] - 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin - 2-ylamine (100 mg, 0.234 mmol) in DME (2 mL) was added Pd (dppf) 2Cl2.CH2Cl2 (10 mg, 0.012 mmol) and Cs2CO3 (351 mg, 0.702 mmol). The mixture was bubbled with nitrogen for 10 minutes then treated by microwave at 150 ° C for 30 minutes. LCMS verified that the reaction was completed. The mis

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The raw reaction mixture was diluted with ethyl acetate followed by washes with water and brine. The solution was dried over MgSO4. Purification by HPLC-prep. provided a solid. The solid was stirred with 4N HCl / dioxane (3 ml) for 3 hours at room temperature. The removal of volatiles induced a residue that was purified by HPLC-prep. to provide (6-amino-3-aza-bicyclo [3,1,0] hex-3-yl) - (4- {6 amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) -methanone (30 mg, 26% yield).

Procedure 36: using Example 1 - 636

[000264] To a mixture of 6'-amino-5 '- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - [3,3'] bipyridinyl-6-ol (78 mg, 0 , 20 mmol), triphenylphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) were added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPhs (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel using gradient elution of dichloromethane, methanol to provide 5- [1- (2,6-Dichloro-3fluor-phenyl) -ethoxy] -6 '- (2-morfolin-4 -yl-ethoxy) - [3,3 '] bipyridinyl-6-ylamine (53

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150/470 mg, 53%).

Procedure 37: using Example 1 - 650

[000265] 3- (2,6-Dichloro-3-fluoro-benzyloxy) - 5-thiazol-2-yl-pyridin-2ylamine: To a microwave tube equipped with a stir bar was added iodine starting material pyridyl (300 mg, 0.702 mmol), tetracis (triphenylphosphine) palladium (0) (40 mg, 5 mol%) and tetrahydrofuran (anhydrous, 6 ml). The vial was capped and purged with nitrogen for 5 minutes. 2-Thiazolylzinc bromide (0.5 M in THF,

1.4 mmol, 2.8 mL) was then added via syringe. The frasconette was heated to 120 ° C in the microwave for 10 minutes. TLC (1: 1 ethyl acetate: methylene chloride) showed a large amount of starting material remaining. Additional 2-thiazolylzinc bromide (0.5 M in THF, 500 pL) was added and the vial was heated at 120 ° C in the microwave for 20 minutes. TLC (1: 1 ethyl acetate: methylene chloride) showed a large amount of starting material remaining. Additional 2-thiazolylzinc bromide (0.5 M in THF, 500 pL) was added and the vial was heated at 120 ° C in the microwave for 60 minutes. TLC (1: 1 ethyl acetate: methylene chloride) also showed a large amount of starting material still remaining, but it also became very cloudy. The contents of the flask were poured into a saturated NH4Cl solution (10 mL) and this solution extracted with ethyl acetate (2 x 30 mL). The combined ethyl acetate layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g prepackaged silica gel column and 1: 1 ethyl acetate: methylene chloride used to elute the desired product (40 mg, 15%).

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Procedure 38: using Example 1 - 652 / = \

[000266] 3- [1- (2,6-Dichloro-3-fluoro-phenyl) -ethoxy] - 5- (1-methyl-1 H-imidazole-

2-yl) -pyridin-2-ylamine: N-methyl imidazole (92 mg, 1.1 mmol) was dissolved in tetrahydrofuran (anhydrous, 4 mL) in a 50 mL circular base flask. The flask was cooled with a dry ice / acetone bath under a nitrogen atmosphere. N-butyl lithium (2.5 M, 562 pL, 1.4 mmol) was added via syringe in 100 pL portions over 5 minutes. The reaction was stirred at -70 ° C for 30 minutes. Solid zinc chloride (anhydrous, 383 mg, 2.8 mmol) was added and the reaction stirred for 15 minutes. The ice bath was then removed and the reaction allowed to warm to room temperature. Once all the zinc chloride was in solution and the reaction at room temperature, iodine scaffolding (400 mg, 0.936 mmol) was added in tetrahydrofuran (anhydrous, 4 mL), followed by tetra-cis (triphenylphosphine) palladium (0) (106 mg 10 mol%) and the reaction heated to reflux. The reaction was monitored by LC / MS until all starting iodine scaffolding was consumed. The reaction was allowed to cool and then diluted with a saturated NH4Cl solution (20 mL). This solution was extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g pre-packed silica gel column and 10% methanol: ethyl acetate was used to elute the desired product (25 mg, 7%).

General Procedure 39: using Example 1 - 657

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[000267] 6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] nicotinonitrile (400 mg, 1.23 mmol) in 70 ml of methanol dried at 0 ° C was bubbled HCl gas for 3 minutes. Stirred overnight at ° C. The volatiles removed and the solids washed with diethyl ether to quantitatively produce the imidate. To 200 mg of the imidate in 4 ml of methanol at 0 ° C, 2N of methylamine in THF (837 gL) was added. Left to stir at 0 ° C for about 1 hour then allowed to warm to room temperature. The volatiles were removed and the residue was chromatographed with 10 - 20% methanol / dichloromethane to produce 70 mg of product.

General Procedure 40:

1. 6-Nitro-5-hydroxynicotinic acid (B2): To a solution of 5-hydroxynicotinic acid (B1) (7.0 g, 50 mmoles) in concentrated H2SO4 was added 9 ml of steaming HNO3 (90%) (9 mL). The reaction mixture was stirred at 55 - 60 ° C in a sealed tube for four days. The mixture was then poured onto ice and the pH was adjusted to 3 with 50% NaOH. MgSO4 was added to saturate the aqueous mixture, which was then extracted with isopropyl alcohol (4 x 45 ml). After removing isopropyl alcohol under reduced pressure,

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5.93 g (64% yield) of B2 was obtained as a yellow solid. MS (APCl), (M + H) ⁺ 185. ^{1 H} NMR (DMSO-d6) δ 8.01 (d, 1 H, Ar-H), 8.41 (d, 1 H, Ar-H).

2. 2,6-Dichlorobenzyl-6-nitro-5 - [(2,6-dichlorobenzyl) oxy] nicotinate (B3): 6-nitro-5-hydroxynicotinic acid (B2) (3.4 g, 18.5 mmoles ), 2,6-dichlorobenzyl bromide (8.88 g, 37 mmoles), DIPEA (5.5 g, 42.5 mmoles) were dissolved in DMF (25 ml) in a 250 ml circular base flask and the The reaction was stirred at room temperature for 4.5 hours and then concentrated under reduced pressure. The resulting mixture was poured out on ice and filtered. The collected solid was dried under reduced pressure to provide 4.25 g (46% yield) of B3. MS (APCl) (M + H) ⁺ 503. ^{1 H} NMR (DMSO-d6) δ 5.47 (s, 2 H, ArCH2O), 5.71 (s, 2 H,

ArCH2O), 7.24 - 7.43 (m, 6 H, Ar-H), 8.26 (d, 1 H, Ar-H), 8.66 (d, 1 H, ArH).

3. 2,6-Dichlorobenzyl-6-amino-5 - [(2,6-dichlorobenzyl) oxy] nicotinate (B4): A mixture of 2,6-dichlorobenzyl-6-nitro-5 - [(2,6dichlorobenzyl) oxy] nicotinate (B3) (5.5 g, 10.96 mmoles), iron powder (0.92 g,

16.43 mmoles), glacial acetic acid (20 ml) and methanol (17 ml) was stirred at 85 ° C for three hours. The reaction mixture was concentrated close to dryness, and ammonium hydroxide (30%) was added to neutralize the mixture. Minimum amount of DMF was added to dissolve the reaction mixture, which was purified by flash column chromatography (eluent: EtOAc - EtOH, 9: 1) to provide 4.5 g (67%) of B4 as a light yellow solid. MS (APCl) (M + H) ⁺ 473.

4. 6-Amino-5 - [(2,6-dichlorobenzyl) oxide] nicotinic acid (B5):

A mixture of 2,6-dichlorobenzyl-6-amino-5 - [(2,6dichlorobenzyl) oxide] nicotinate (B4) (3.5 g, 7.4 mmol), lithium hydroxide (0.41 g, 17 mmol) ), water (22 ml) and methanol (30 ml) was stirred and refluxed at 85 ° C for 5 hours. The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in water,

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154/470 extracted with a mixture of Et2Ü / hexane (1: 1.4 x 25 mL), neutralized with 1N HCl to form a white precipitation, which was filtered and dried under reduced pressure to provide 1.83 grams (79% ) of B5 as a white solid. MS (APCl) (M + H) ⁺ 313. ^{1 H} NMR (DMSO-d6) δ 5.26 (s, 2 H, ArCH2O), 6.37 (s, 2 H, NH2), 7.43 - 7 , 48 (t, 1 H, Ar-H), 7.54 (s, 2 H, Ar-H), 7.56 (s, 1 H, Ar-H), 8.18 (s, 1 H, Ar-H).

[000268] To a group of 400 μL of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 μL (0.2 M in DMF) of 4- [6-amino-5- acid (2,6-dichloro-3-fluoro-benzyloxy) pyridin-3-yl] -benzoic acid, 80 μL of triethylamine (1M in DMF) and 160 μL of HATU (0.5 M in DMF) and the reactions were stirred at 70 ° C for 2 hours. The solvent was removed using the SpeedVac device and the crude reaction mixtures were redissolved in DMSO and transferred using a liquid manipulator to a 96 ml 1 well plate to provide a final theoretical concentration of ~ 10 mM. The reactions were analyzed and the positive product was identified using LC / MS. The stock solution was diluted to 50 nM and tested for the percentage of cMET inhibition at 50 nM.

General Procedure 41:

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COOH

HATH, DMF, ° C, 2hr

CONR'R [000269] To a group of 400 pL of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 pL (0.2 M in DMF) of 6-Amino-5- acid [(2,6-dichlorobenzyl) oxy] nicotinic, 80 pL of triethylamine (1 M in DMF) and 160 pL of HATU (0.5 M in DMF) and the reactions were stirred at 70 ° C for 2 hours. The solvent was removed using the SpeedVac device and the raw reaction mixtures were redissolved in DMSO and transferred using a liquid handler to a 96 well plate to provide a theoretical final concentration of ~ 10 mM. The reactions were analyzed and the identification of a positive product was made using LC / MS. The stock solution was diluted to 1 pM and tested.

General Procedure 42:

[000270] [4- (6-Amino-5-hydroxy-pyridin-3-yl) -phenyl] - (4-pyrrolidin-1-ylpiperidin-1-yl) -methanone: To a solution of [4- (6 -Amino- 5-benzyloxy pyridin-3-yl) -phenyl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone (3.67 g, 8.1 mmol) in 100 mL of ethanol was 25 ml of cyclohexene and 367 mg of black palladium are added. Reflected during the night. The solution was filtered and the volatiles were removed. To the residue was added 60 ml of MeOH, 20 ml of cyclohexene and 350 mg of black Pd. Refluxed during the night. The volatiles were filtered and removed, resuspended in methanol, 350 mg of black Pd added and hydrogenated at 1 atm overnight (pressure reactors all active). Filtered and isolated 3.0 grams of a solid foam. ^{1 H} NMR (400 MHz, DMSO-d6) δ ppm 7.62 (d, J = 2.02 Hz, 1 H), 7.58 (d, J = 8.34 Hz, 2 H), 7.41 (d, J = 8.34 Hz, 2 H), 7.12 (d, J = 2.02 Hz, 1 H), 5.74 (s, 2 H), 3.33 (s, 5 H) , 3.08 (s, 2 H),

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1.95 (m, 8 H), 1.49 (s, 2 H). LC / MS (APCl) 367 m / e (M + 1).

[000271] To a group of 10 x 75 mm test tubes were added [4- (6-Amino-5-hydroxy - pyridin-3-yl) -phenyl] - (4-pyrrolidin-1-ylpiperidin-1- il) -methanone (0.2 M in DMF, 80 qmol, 1.0 eq.), Cs2CO3 (2 M, 160 qmol, 2.0 equiv) and different alkyl halides (0.2 M in DMF, 88 qmol , 1.1 eq.). The reactions were stirred at room temperature overnight. In order to separate the inorganic salts, the resulting suspension was evaporated and DMF (625 qL) was added. After stirring, the mixture was centrifuged to settle the solid residue, and the supernatant was transferred to a new 10 x 75 mm test tube. The reactions were analyzed and the positive product was identified using LC / MS. The raw material solution was diluted to 1 qM and tested.

General procedure 43:

NH, [000272] (2R, 6S) -4-4- (6-Amino-5hydroxy-pyridin-3-yl) -benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester : See general IG procedure. 83.5% yield. ^{1 H} NMR (400 MHz, DMSO-D6) δ ppm 7.81 (d, J = 2.27 Hz, 1 H) 7.57 (d, J = 8.34 Hz, 2 H) 7.41 (d , J = 8.34 Hz, 2 H) 7.12 (d, J = 2.02 Hz, 1 H) 5.70

nh ₂ nh.

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157/470 (s, 2 H) 4.07 (s, 2 H) 3.31 (s, 3 H) 1.39 (s, 10H) 1.03 - 1.14 (m, 7 H). [000273] To a group of 10 x 75 mm test tubes were added [4- (6-Amino-5-hydroxy-pyridin-3-yl) -phenyl] - (4-pyrrolidin-1-yl-piperidin-

1- yl) -methanone (0.2 M in DMF, 80 pmol, 1.0 eq.), Cs2CO3 (2 M, 160 pmol, 2.0 equiv) and different alkyl halides (0.2 M in DMF, 88 pmol, 1.1 eq.). The reactions were stirred at room temperature overnight. In order to separate the inorganic salts, the resulting suspension was evaporated and DMF (625 pL) was added. After stirring, the mixture was centrifuged to settle the solid residue, and the supernatant was transferred to a new 10 x 75 mm test tube. The solid residues were extracted with more DMF (400 pL) and the extracts were combined with the first organic layer. The DMF was evaporated, and HCl (4 M in dioxane, 2.5 mmoles, 31 eq.) Was added to the reaction mixture in the receiving test tube. The reaction mixture was stirred at room temperature for 3 hours. The reactions were analyzed and the positive product was identified using LC / MS. The stock solution was diluted to 1 pM and tested.

Example I (a):

1. To a stirred solution of Cs2CO3 (11.63 g, 35.69 mmol) in DMF (180 mL) under an N2 atmosphere containing 3-hydroxy-4-nitro-pyridine (5 g, 35.69 mmol) was added bromide of 2,6dichlorobenzyl (8.56 g, 35.69 mmoles). The mixture was stirred for 6 hours at room temperature. The reaction was then diluted with EtOAc (400 ml) and partitioned with H2O (100 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The organic layers were then combined and washed with H2O (2 x 50 ml) and brine (1 x 50 ml). The organics were dried over Na2SO4, filtered and concentrated to dryness under vacuum to produce 3- (2,6-dichloro-benzyloxy) -

2-nitro-pyridine (10.5 g, 98.4%) as a white solid.

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2. To a stirred mixture of AcOH (650 mL) and EtOH (500 mL), 3- (2,6-dichloro-benzyloxy) - 2-nitro-pyridine (37.4 g, 0.11 mol) iron (69.4 g, 0.11 mol). The reaction was slowly heated to reflux and allowed to stir for 1 hour. The reaction was cooled to room temperature then filtered through a pad of celite. The resulting filtrate was neutralized with concentrated NH4OH (600 ml) and then extracted with EtOAc (3 x 500 ml). The combined organic extracts were washed with saturated NaHCO3 (2 x 100 ml), H2O (2 x 100 ml) and brine (1 x 100 ml) then dried (Na2SO4), filtered and concentrated to dryness in vacuo to produce 3- (2,6-dichloro-benzyloxy) -pyridin-2-ylamine (32.4 g, 0.11 mol, 99%) as a light yellow solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.56 (m, 3 H), 7.46 (dd, 2 H), 7.36 (d, 1 H), 6.62 (dd, 1 H ), 6.18 (br s, 2 H, NH2), 5.24 (s, 2 H); MS m / z 270 [M + 1].

3. A stirred solution of 3- (2,6-dichloro-benzyloxy) -pyridin-

2-ylamine (32.4 g, 0.11 mol) in acetonitrile was cooled to 0 ° C using an ice bath. To this solution was added Nbromosuccinimide (19.5 g, 0.11 mol) in portions. The reaction was stirred at 0 ° C for 15 minutes. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 ml) and partitioned with H2O (250 ml). The organic was then washed with saturated NaHCO3 (2 x 200 ml) and brine (1 x 200 ml). Activated charcoal was added to the organic layer and heated to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum at one third of the original volume. The solids were then filtered to produce 5-bromo-3- (2,6-dichlorobenzyloxy) -pyridin-2-ylamine (22.0 g, 0.07 mol, 64%) as a tan solid. The remaining filtrate was concentrated in vacuo to yield crude 5-bromo-3- (2,6-dichloro-benzyloxy) -pyridin-2-ylamine (12.1 g,

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0.04 mol, 35%) as a brown solid.

Example I (b):

[000274] 3-Benzyloxy - 5-bromo-pyridin-2-ylamine was prepared following procedure 1 from 3-benzyloxy - pyridin-2-ylamine as a tan solid in 65% production.

Example I (c):

[000275] 5-Bromo-3- (2,6-difluoro-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2,6-difluoro-benzyloxy) - 2-nitropyridine was prepared 99% production. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.14 (m, 2 H), 7.79 (dd, 1 H), 7.52 (m, 1 H), 7.16 (m, 2 H ),

5.37 (s, 2 H); MS m / z 266 [M +]. 3- (2,6-Diflúor-benzyloxy) -pyridin-2ylamine was prepared in 100% production. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2 H), 7.64 (dd, 1 H), 7.57 (m, 2 H), 6.84 (dd, 1 H), 5.24 (s, 2 H); MS m / z 237 [M + 1]. 5-Bromo-3- (2,6-difluoro-benzyloxy) pyridin-2-ylamine was prepared in 91% production.

Example I (d):

[000276] 5-Bromo-3- (2-bromo-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. The intermediate of 3- (2-bromobenzyloxy) - 2-nitro-pyridine was prepared in 99% production as a white solid. 3- (2-bromo-benzyloxy) -pyridin-2-ylamine was prepared in 100% production as a solid. 5-Bromo-3- (2-bromo-benzyloxy) pyridin-2-ylamine was obtained in 37% of production as a tan solid.

Example I (e):

[000277] 5-Bromo-3- (2-chloro-6-fluor-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2-chloro-6-fluor-benzyloxy) -

2-nitro-pyridine was prepared in 90% of production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.15 (m, 2 H), 7.80 (m, 1 H), 7.50 (m, 1 H), 7.40 (m, 1 H ), 7.30 (m, 1 H), 5.39 (s, 2 H).

3- (2-chloro-6-fluoro-benzyloxy) -pyridin-2-ylamine was prepared in 88%

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160/470 production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.70 - 7.15 (m, 5 H), 6.45 (m, 1 H), 5.45 (br s, 2 H), 5.06 (s, 2 H). 5Bromo-3- (2-chloro-6-fluoro-benzyloxy) -pyridin-2-ylamine was prepared in 81% production.

Example I (f):

[000278] 5-Bromo-3- (2-chloro-4-fluor-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2-chloro-4-fluor-benzyloxy) -

2-nitro-pyridine was prepared in 91% of production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.08 (m, 2 H),

7.75 (m, 1 H), 7.63 (m, 1 H), 7.55 (m, 1 H), 7.25 (m, 1 H), 5.45 (s, 2 H).

3- (2-chloro-4-fluoro-benzyloxy) -pyridin-2-ylamine was prepared in 100% production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.70 (m, 2 H), 7.47 (m, 1 H), 7.20 (m, 1 H), 7.08 (m, 1 H ), 6.45 (m, 1 H), 5.62 (br s, 2 H), 5.08 (s, 2 H). 5-Bromo-3- (2-chloro-4-fluoro-benzyloxy) pyridin-2-ylamine was prepared in 63% production.

Example I (g):

[000279] 5-Bromo-3- (2,4-dichloro-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2,4-Dichloro-benzyloxy) - 2-nitro-pyridine was prepared at 96% production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.05 - 7.50 (m, 6 H), 5.39 (s, 2 H); MS (m / z) 299 (M + 1). 3- (2,4-Dichloro-benzyloxy) -pyridin-2-amine was prepared in 98% production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.65 - 6.25 (m, 6 H), 5.85 (br s, 2 H), 5.06 (s, 2 H). 5-Bromo-3- (2,4-dichloro-benzyloxy) -pyridin-2-ylamine was prepared in 65% production.

Example I (h):

[000280] 2- (2-Amino-5-bromo-pyridin-2-yloxymethyl) -benzonitrile was prepared following procedure 1. 2- (2-Nitro-pyridin-3yloxymethyl) -benzonitrile was prepared in 91% of production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.15

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7.55 (m, 1 H), 5.50 (s, 2 H). 2- (2-Amino-pyridin-3-yloxymethyl) -benzonitrile was prepared in 86% of production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.95 - 6.45 (m, 7 H), 5.65 (br s, 2 H), 5.20 (s, 2 H). 2- (2-Amino-5-bromo-pyridin-3-yloxymethyl) -benzonitrile was prepared in 77% production.

Example I (i):

[000281] 5-Bromo-3- (2-trifluoromethyl-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2-trifluoromethyl-benzyloxy) -

2-nitro-pyridine was prepared in 92% of production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.05 - 7.58 (m, 7 H), 5.45 (s, 2 H). 3- (2-trifluoromethyl-benzyloxy) -pyridin-2-ylamine was prepared in 80% production as a tan solid. 5Bromo-3- (2-chloro-4-fluoro-benzyloxy) -pyridin-2-ylamine was prepared in 43% production as a solid.

Example I (j):

[000282] 5-Bromo-3- (4-tert-butyl-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (4-tert-butyl-benzyloxy) - 2-nitro-pyridine was prepared 80% production as an oil. ^{1 H} NMR (400 MHz, DMSO-d6) 8.10 - 7.30 (m, 7 H), 5.30 (s, 2 H), 1.25 (s, 9H). 3- (4-tert-Butyl-benzyloxy) -pyridin-2-amine was prepared in 100% production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.45 - 6.25 (m, 7 H), 5.58 (br s, 2 H), 5.05 (s, 2 H), 1.25 (s, 9H). 5Bromo-3- (4-tert-butyl-benzyloxy) -pyridin-2-ylamine was prepared in 55% production as a solid.

Example I (k):

[000283] 5-Bromo-3- (2-chloro-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. 3- (2-Chloro-benzyloxy) - 2-nitro-pyridine was prepared in 89 % of production as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.10 - 7.40 (m, 7 H), 5.40 (s, 2 H). 3- (2-Chloro-benzyloxy) -pyridin-2-ylamine was prepared in 100%

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162/470 production as a tan solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 8.65 - 6.45 (m, 7 H), 5.62 (br s, 2 H), 5.10 (s, 2 H). 5-Bromo-3- (2-chlorobenzyloxy) -pyridin-2-ylamine was prepared in 22% production as a solid.

Example I (l):

[000284] 5-Bromo-3- (2-chloro-3,6-difluor-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. The intermediate of 3- (2-chloro-3,6-difluor -benzyloxy) - 2-nitro-pyridine was prepared in 99% production as a not entirely white solid. ^{1 H} NMR (CDCh, 300 MHz) δ 5.31 (s, 2 H), 7.02 - 7.09 (dt, 1 H, J, 4, 8), 7.17 - 7.23 (dt, 1 H, J, 4.5, 8.4), 7.54 - 7.58 (dd, 1 H, J, 4.5, 8.4), 7.71 - 7.68 (dd, 1 H , J, 1.21, 8.4), 8.14 - 8.16 (dd, 1 H, J, 1.23, 4.5). 3- (2-chloro-3,6-difluoro-benzyloxy) pyridin-2-ylamine was prepared in 100% production as a light yellow solid. ^{1 H} NMR (CDCl3, 300 MHz) δ 4.6 - 4.8 (brs, 2 H), 5.2 (s, 2 H), 7.0 - 7.08 (dt, 1 H, J, 4 , 1, 9.0), 7.09 - 7.12 (dd, 1 H, J, 1.0, 7.8), 7.15 - 7.22 (dt, 1 H, J, 4.8 , 8.0), 7.69 - 7.71 (dd, 1 H, J, 1.2, 5.1). 5Bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-ylamine was obtained in 64% of production as a tan solid.

Example I (m):

[000285] 5-Bromo-3- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyridin-2ylamine was prepared following procedure 1 starting from 3hydroxy - 4-nitro-pyridine and 1-bromomethyl-3-fluorine- 2-trifluoromethyl-benzene. Example I (n):

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 ml, 0.5 M) at 0 ° C using an ice bath for 10 minutes. Lithium aluminum hydride (2.75 g, 0.072 mol) was added slowly. The reaction was stirred at room temperature for 3 hours. The reaction was cooled in an ice bath, and water (3 ml) was added in drops followed by the addition of 15% NaOH (3 ml) slowly. The mixture was stirred at room temperature

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163/470 room for 30 minutes. 15% NaOH (9 mL), MgSÜ4 were added and the mixture filtered to remove the solids. The solids were washed with THF (50 ml) and the filtrate was concentrated to provide 1- (2,6-Dichloro-3-fluoro-phenyl) -ethanol (14.8 gm, 95% yield) as a yellow oil. ^{1 H} NMR (400 MHz, DMSO-d6) δ 1.45 (d, 3 H),

5.42 (m, 2 H), 7.32 (m, 1 H), 7.42 (m, 1 H).

2. To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) and DEAD (13.65 ml of a 40% solution in toluene) in THF (200 ml) at 0 ° C was added a solution of 1- (2,6-dichloro-3-fluorophenyl) -ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting light orange solution was stirred under a nitrogen atmosphere at room temperature for 4 hours, at which point all starting materials were consumed. The solvent was removed, and the crude material was loaded dry on silica gel, and eluted with ethyl acetate - hexanes (20: 80) to produce 3 (2,6-dichloro-3-fluoro-benzyloxy) - 2-nitro- pyridine (6.21 g, 0.021 mol, 98%) as a pink solid. ^{1 H} NMR (CDCfe, 300 MHz) δ 1.8 - 1.85 (d, 3 H), 6.0 - 6.15 (q, 1 H), 7.0 - 7.1 (t, 1 H ), 7.2 - 7.21 (d, 1 H), 7.25 - 7.5 (m, 2 H), 8.0 - 8.05 (d, 1 H).

3. 3- (2,6-dichloro-3-fluoro-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. A stirred mixture of AcOH (650 mL) and EtOH (500 mL) was suspended 3- (2,6-dichloro-3-fluorobenzyloxy) - 2-nitro-pyridine (9.43 g, 0.028 mol) and iron flakes (15.7 g, 0.28 mol). The reaction was slowly heated to reflux and allowed to stir for 1 hour. The reaction was cooled to room temperature then diethyl ether (500 ml) and water (500 ml) were added. The solution was carefully neutralized by the addition of

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164/470 sodium carbonate. The combined organic extracts were washed with saturated NaHCO3 (2 x 100 ml), H2O (2 x 100 ml) and brine (1 x 100 ml) then dried (Na2SO4), filtered and concentrated to dryness in vacuo to produce 3- (2,6-dichloro-3-fluoro-benzyloxy) -pyridin-

2-ylamine (9.04 g, 0.027 mol, 99%) as a light pink solid. ^{1 H} NMR (CDCl3, 300 MHz) δ 1.8 - 1.85 (d, 3 H), 4.9 - 5.2 (brs, 2 H), 6.7 -

6.84 (q, 1 H), 7.0 - 7.1 (m, 1 H), 7.2 - 7.3 (m, 1 H), 7.6 - 7.7 (m, 1 H ).

4. 5-bromo-3- (2,6-dichloro-3-fluoro-benzyloxy) -pyridin-2-ylamine was prepared following procedure 1. A stirred solution of

3- (2,6-dichloro-3-fluoro-benzyloxy) -pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0 ° C using an ice bath. To this solution was added NBS (5.33 g, 0.03 mol) in portions. The reaction was stirred at 0 ° C for 15 minutes. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 ml), and purified by chromatography on silica gel. The solvents were then removed in vacuo to produce 5bromo-3- (2,6-dichloro-3-fluoro-benzyloxy) -pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid .

Example I (o):

1. 2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) was dissolved in THF (0.2 M) and stirred at 0 ° C for 5 minutes. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added. The reaction was gradually warmed to room temperature and stirred for 2 hours. Methanol, and 1N HCI were added to the mixture and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to provide 1- (2-chloro-3,6-difluoro-phenyl) -ethanol as oil. ^{1 H} NMR (400 MHz, DMSO-d6) δ 1.42 (d, 3 H), 5.21 (m, 1 H), 5.42 (m, 1 H), 7.09

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165/470 (m, 1 H), 7.18 (m, 1 H).

2. 5-bromo-3- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-2ylamine was prepared following the same procedure as in Example I (n) starting from 1- (2-chloro-3,6-difluoro-phenyl) -ethanol and 3-hydroxy nitropyridine.

Example II (a):

[000286] To an ice-cooled solution of (2,6-dichloro-phenyl) methanol (5 g, 28.2 mmoles) in anhydrous tetrahydrofuran (200 ml) was added sodium hydride (1.13 g, 28, 2 mmoles, 60% available) slowly under a nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromo-pyrazin-2-ylamine (7.08 g, 28.2 mmoles) in anhydrous tetrahydrofuran (50 ml) was added via an addition funnel. Once the addition was completed the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reverse phase HPLC. After 18 hours HPLC showed that the majority of starting 3,5dibromo-pyrazin-2-ylamine was consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated in vacuo until 50 ml remained. The mixture was diluted with ethyl acetate (200 ml) and extracted with 50% brine (2 x 200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified using a silica gel column eluting with 1: 1 ethyl acetate / dichloromethane to produce 5-bromo-3- (2,6-dichloro-benzyloxy) -pyrazin-

2-ylamine as a white solid (8.17 g, 83% yield).

Example II (b):

[000287] 5-Bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-ylamine was prepared following procedure 2 of (2-chloro-3,6-difluorophenyl) -methanol and 3,5-dibromo-pyrazin-2-ylamine.

Example II (c):

1. 2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent)

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166/470 was dissolved in THF (0.2 M) and stirred at 0 ° C for 5 minutes. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added. The reaction was gradually warmed to room temperature and stirred for 2 hours. HCl methanol and 1N were added to the mixture and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to provide 1- (2-chloro-3,6-difluoro-phenyl) -ethanol as an oil. ^{1 H} NMR (400 MHz, DMSO-d6) δ 1.42 (d, 3 H), 5.21 (m, 1 H), 5.42 (m, 1 H), 7.09 (m, 1 H ), 7.18 (m, 1 H).

2. 5-bromo-3- [1- (2-chloro-3,6-diflúor-phenyl) -etóxi] -pyrazin-2ilamina was prepared following procedure 2 of 1- (2-chloro-3,6diflúor -phenyl) -ethanol and 3,5-dibromo-pyrazin-2-ylamine.

Example II (d):

1. 1- (2-Chloro-3,6-difluoro-phenyl) - 2-methyl-propan-1-ol was prepared following the procedure of Example II (c) using isopropylmagnesium chloride. ^{1 H} NMR (400 MHz, DMSO-d6) δ 0.63 (d, 3 H), 1.06 (d, 3 H), 2.19 (m, 1 H), 4.59 (m, 1 H ), 5.54 (d, 1 H), 7.21 (m, 1 H), 7.36 (m, 1 H).

2. 5-bromo-3- [1- (2-chloro-3,6-difluoro-phenyl) - 2-methyl-propoxy] pyrazin-2-ylamine was prepared following procedure 2 of 1- (2-chloro- 3,6-difluoro-phenyl) - 2-methyl-propan-1-ol and 3,5-dibromo-pyrazin-2-amine.

Example II (e):

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 ml, 0.5M) at 0 ° C using an ice bath for 10 minutes. Lithium aluminum hydride (from Aldrich, 2.75 g, 0.072 mol) was added slowly. The reaction was stirred at room temperature for 3 hours. The reaction was cooled in an ice bath, and water (3 ml) was added in drops followed by the addition of 15% NaOH (3 ml) slowly. The mixture was stirred

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167/470 at room temperature for 30 minutes. 15% NaOH (9 mL), MgSÜ4 were added and the mixture filtered to remove the solids. The solids were washed with THF (50 ml) and the filtrate was concentrated to provide 1- (2,6-Dichloro-3-fluoro-phenyl) -ethanol (14.8 gm, 95% yield) as a yellow oil. ^{1 H} NMR (400 MHz, DMSO-d6) δ

1.45 (d, 3 H), 5.42 (m, 2 H), 7.32 (m, 1 H), 7.42 (m, 1 H).

2. 5-Bromo-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-amine was prepared following procedure 2 of 1- (2,6-dichloro-2)

3-fluorine-phenyl) -ethanol and 3,5-dibromo-pyrazin-2-ylamine.

Example II (f):

[000288] 5-Bromo-3- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2ylamine was prepared following procedure 2 of (3-fluoro-2trifluoromethyl-phenyl) -methanol and 3,5-dibromo -pyrazin-2-ylamine.

Example I - 1:

[000289] A mixture of 5-bromo-3- (2,6-dichloro-benzyloxy) -pyridin-2-amine (example I (a), 100 mg, 0.29 mmol), 4- (4.4.5, 5-tetramethyl-1,3-2dioxabordan-2-yl) phenol (86 mg, 0.35 mmol), bis (triphenylphosphine) palladium (II) chloride (8 mg, 0.009 mmol) and sodium carbonate (91 mg, 0.87 mmol) in ethylene glycol dimethyl ether (10 mL) and water (0.5 mL) was heated to reflux under nitrogen for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica column to yield 4- [6-amino-5 (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenol as crystals of clear pin (89 mg, 85% yield).

Example I - 2:

1. To a mixture of 4- (4,4,5,5-tetramethyl-1,3-2dioxabordan-2-yl) phenol (5.00 g, 22.72 mmoles) and Cs2CO3 (16.29 g, 49 , 98 mmoles) in DMF (100 ml) 4 (2-chloroethyl) morpholine hydrochloride (4.65 g, 24.99 mmoles) and Kl (0.2 g, 0.6 mmol) were added. THE

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168/470 mixture was stirred at 65 ° C, oil bath overnight and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (600 ml), and divided with water. The water layer was extracted with ethyl acetate (2 X 50 ml). The combined ethyl acetate solution was washed with brine (5 X 100 mL), dried over Na2SO4, filtered, condensed, and dried in a high vacuum to provide 4- {2- [4- (4,4,5,5- tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] ethyl} -morpholine (6.8 g, 90% yield) as a not entirely white solid. ^{1 2 H} NMR (400 MHz, DMSO-d6) δ 7.55 (d, 2 H), 6.90 (d, 2 H), 4.07 (t, 2 H), 3.54 (m, 4 H), 2.65 (t, 2 H), 2.43 (m, 4 H).

2. 3- (2,6-Dichloro-benzyloxy) - 5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] pyridin-2-ylamine was prepared from 5-bromo-3- (2, 6-dichloro-benzyloxy) pyridin-2-ylamine (example I (a)) and 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) -phenoxy] -ethyl} -morpholine (prepared in part 1) following procedure 3 as a white solid.

Example I - 3:

1. 3- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenoxy] -ethyl} -morpholine was prepared following the same procedure as 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] ethyl} -morpholine in Example I - 2 using 3- ( 4,4,5,5-tetramethyl1,3-2-dioxabordan-2-yl) phenol in 92% production as a white wax solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.28 (t, 1 H), 7.22 (dt,

H), 7.14 (d, 1 H), 7.04 (ddd, 1 H), 4.06 (t, 2 H), 3.56 (m, 4 H), 2.49 (t,

H), 2.45 (m, 4 H).

2. 3- (2,6-Dichloro-benzyloxy) - 5- [3- (2-morpholin-4-yl-ethoxy) -phenyl] pyridin-2-ylamine was prepared from 5-bromo-3 - (2, 6-dichloro-benzyloxy) Petition 870190089642, of 10/09/2019, p. 173/482

169/470 pyridin-2-ylamine (example I (a)) and 3- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy ] -ethyl} -morpholine prepared in part 1 following procedure 3 as a light yellow solid.

Example I - 4:

1. To a mixture of 4-bromoindole (9.80 g, 50 mmoles), pinacol diborate (13.97 g, 55 mmoles), and KOAc (14.72 g, 150 mmoles) in DMSO (200 mL) was PdCl2 (dppf) CH2Cl2 of palladium catalyst (1.22 g, 1.5 mmol) is added. The system was degassed, and then charged with nitrogen three times. The mixture was stirred at 80 ° C, oil bath under nitrogen for 22 hours. TLC showed the complete disappearance of the 4bromoindole starting material. The mixture was cooled to room temperature, and then poured into water (1 L). The product was extracted with ethyl acetate three times. The combined extracts were washed with brine five times to remove the DMSO solvent, and then dried over Na2SO4. During the washing step, the catalyst may precipitate, which was removed by filtration. The ethyl acetate solution was filtered and condensed. The residue was purified on a silica gel column eluting with EtOAc - hexane (9: 1). The first fraction provided the side product of indole (1.25 g, 21% yield), Rf 0.55 (EtOAc - hexane 5: 1). The second fraction provided

4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -1 H-indole as a white solid (8.01 g, 66%), Rf 0.46 ( EtOAc - hexane 5: 1). ^{1 H} NMR (300 MHz, DMSO-d6): δ 11.03 (bs, 1 H, NH)), 7.49 (d, J 7.7 Hz, 1 H, H-5),

7.38 (dd, J 0.9 Hz, J 7.0 Hz, 1 H, H-7), 7.38 (t, J 2.6 Hz, 1 H, H-2), 7.06 ( dd, J 7.7 Hz, J 7.0 Hz, 1 H, H-6), 6.73 (bd, J 2.2 Hz, 1 H, H-3), 1.32 (s, 12 H , 4CH3); MS (m / e): 244 (M + H) ⁺ .

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2. 3- (2,6-dichloro-benzyloxy) - 5- (1 H-indol-4-yl) -pyridin-2-amine was prepared from 5-bromo-3 - (2,6-dichloro-benzyloxy) -pyridin - 2ylamine (Example I (a)) and 4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan- 2-yl) 1 H-indole following procedure 3. The first fraction has been identified to be 3- (2,6-dichloro-benzyloxy) - 5- (1 H-indol-4-yl) -pyridin-2-ylamine. Example I - 5:

[000290] The same experiment was carried out as Example 4, and the second fraction was identified as 3- [2-chloro-6- (1 H-indol-4-yl) benzyloxy] - 5- (1 H-indol- 4-yl) -pyridin-2-ylamine.

Example I - 6:

[000291] 2- [6-Amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -pyrrole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-3 (2, 6-dichloro-benzyloxy) -pyridin-2-ylamine (Example I (a)) and N-Boc pyrrole-2-boronic acid following procedure 3.

Example I - 7:

[000292] To a tert-butyl ester mixture of 2- [6-amino-

5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -pyrrole-1-carboxylic (Example 6, 30 mg, 0.069 mmol) in ethanol / water (2: 1, 10 mL) was added carbonate sodium (100 mg, 0.95 mmol). The mixture was refluxed overnight. The reaction was cooled to room temperature and extracted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica gel column to yield 3 (2,6-dichloro-benzyloxy) - 5- (1H-pyrrol-2-yl) -pyridin- 2- ilamine.

Examples I - 8 to I - 12:

[000293] The compounds of Examples 1-8 to 1-12 were prepared according to procedure 3 using 5-bromo-3- (2,6dichloro-benzyloxy) -pyridin-2-ylamine and: boronic acid of 4 fluorophenyl (Example I - 8); boronic phenyl acid (Example I - 9); 2-fluorophenyl boronic acid (Example I - 10); boronic acid of 3-fluorophenyl (Example I - 11); and 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)

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171/470 phenylamine (Example I - 12).

Example I - 13:

[000294] To a solution of 5- (4-amino-phenyl) - 3- (2,6-dichlorobenzyloxy) -pyridin-2-ylamine (100 mg, 0.28 mmol) in methylene chloride (5 mL) a At 0 ° C, methanesulfonyl chloride (0.021 ml, 0.28 mmol) and 4-methylmorpholine (0.16 ml) were added. The mixture was stirred at room temperature for 2 hours, and diluted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified with a silica gel column eluting with hexane - ethyl acetate (5: 1) to provide N- {4- [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3- il] -phenyl} methanesulfonamide.

Example I - 14:

[000295] To a solution of 5- (4-amino-phenyl) -3- (2,6-dichlorobenzyloxy) -pyridin-2-ylamine (100 mg, 0.28 mmol) in acetonitrite (3 mL) at 0 ° C, pyridine (0.035 ml, 1.5 eq.) And acetic anhydride (0.03 ml, 0.28 mmol) were added. The mixture was stirred at room temperature overnight, and the precipitate was filtered to provide N- {4- [6-Amino-

5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} -acetamide as a white solid.

Examples I - 15 to I - 35:

[000296] The compounds of Examples I - 15 to I - 35 were prepared according to procedure 3 of 5-bromo-3- (2,6-dichloro-benzyloxy) pyridin-2-ylamine and: 3- (4, 4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (Example I - 15); boronic acid of 4-methoxyphenyl (Example I - 16); 3-aminobenzenoboronic acid (Example I - 17); 4trifluoromethoxybenzenoboronic acid (Example I - 18); boronic acid of 2hydroxybenzene (Example I - 19); 2-phenoxyphenylboronic acid (Example I - 20); 3,4-difluorophenylboronic acid (Example I - 21); (3isopropyl) phenylboronic acid (Example I - 22); acid (2Petition 870190089642, of 10/09/2019, page 176/482

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trifluoromethylphenyl) boronic (Example I - 23); acid (2- methoxyphenyl) boronic acid (Example I - 24); acid (4- trifluoromethylphenyl) boronic (Example I - 25); acid [(2- methylsulfonylamino) phenyl] boronic (Example I - 26); acid 4- hydroxymethylphenylboronic (Example I - 27); acid 3.4- methylenedioxyphenylboronic (Example I - 28); acid 2- trifluoromethoxyphenylboronic (Example I - 29); 4-methylthiophene acid - 2- boronic (Example I - 30); 2-benzyloxyphenylboronic acid (Example I -

31); 3-methoxyphenylboronic acid (Example I - 32); 1- (tert-butoxycarbonyl) indole-2-boronic acid, and the tert-butoxycarbonyl group were removed using 20% trifluoroacetic acid dichloromethane (Example I - 33); (3-fluoro-4-benzyloxyphenyl) boronic acid (Example I - 34); and 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid (Example I - 35).

Example I - 36:

[000297] To a solution of 4- [6-amino- 5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -benzoic acid (50 mg, 0.13 mmol), HOBT (21 mg, 0.156 mmol ), and EDC (30 mg, 0.156 mmol) in DMF (2 mL) was added N, N-diethylethylenediamine (0.022 mL, 0.156 mmol). The reaction was stirred at room temperature for 24 hours, then diluted with EtOAc, and partitioned with H2O. The organic was separated and the aqueous was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness in vacuo. The material was employed using column chromatography (silica gel, 99: 1 to 95: 5 CH2Cl2 / MeOH) to provide 4- [6-amino-5- (2,6dichloro-benzyloxy) -pyridin-3-yl] - N- (2-diethylamino-ethyl) -benzamide (45 mg, 72% yield) as a white solid.

Examples I - 37 and I - 38:

[000298] The compounds of Examples I - 37 and I - 38 were prepared from 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid and

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N, N-diethyl-1,3-propanediamine (Example I - 37) and 1-methylpiperazine (Example I - 38), following procedure 4.

Example I - 39:

1. A mixture of (+) - carbobenzyloxy-D-proline (1.5 g, 6 mmoles), EDC (2.3 g, 12 mmoles), HOBt (800 mg, 6 mmoles), TEA (1.5 mL ) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at room temperature for 18 hours. The reaction was diluted with water and sodium bicarbonate, extracted with dichloromethane (3x). The combined DCM was concentrated and purified on a silica gel column to provide benzyl ester of (R) - 2- (pyrrolidine-1carbonyl) -pyrrolidine-1-carboxylic acid. The benzyl ester of (R) - 2 (pyrrolidine-1-carbonyl) -pyrrolidine-1-carboxylic acid was hydrogenated using Pd / C in methanol at room temperature for 20 hours to provide pyrrolidin-1-yl- (R ) -pyrrolidin-2-yl-methanone. To a solution of pyrrolidin-1-yl- (R) -pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF (10 mL) at 0 ° C was added B2 H6 (10 mL, 10 mmoles). The mixture was heated to reflux for 16 hours. The reaction was acidified with HCl and concentrated. The residue was basified to pH 10 with 2N NaOH and extracted with 5% methanol in DCM. The organic layer was concentrated and purified on a silica gel column to provide 800 mg (73%) of (R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine.

2. {4- [6-Amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -methanone was prepared from 4- [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid and (2R) -

2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4. Examples I - 40 to I - 45:

[000299] The compounds of Examples 1-40 to 1-45 were prepared

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174/470 according to procedure 4 of 4- [6-amino- 5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -benzoic acid and: (2S) - 2-pyrrolidin-1-ylmethyl- pyrrolidine (Example 1 - 40); 4-pyrrolidin-1-yl-piperidine (Example I - 41); ethanol from

4-piperidine (Example 1 - 42); (3S) - (3-dimethylamino-pyrrolidine (Example 1-43); (3R) - (3-dimethylamino-pyrrolidine (Example 1 - 44); and (S) -3cyclopropylaminomethyl-piperidine (prepared according to procedures for (R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine in example 1 - 39) (Example 1 - 45).

Example 1-46:

1. To a solution of epichlorohydrin (from Aldrich, Milwaukee, 3.91 ml, 50.0 mmoles) in EtOH (100 ml) was added pyrrolidine (4.18 ml, 50.0 mmoles) at room temperature. The mixture was stirred at 55 ~ 60 ° C for 20 hours, then refluxed for 3 hours. The solvent was removed under reduced pressure and crude 1-chloro-3-pyrrolidin-1-yl-propan-2-ol was obtained as an oil (10 g). This oily product was dissolved in 7M ammonia in MeOH (40 ml) and stirred at room temperature overnight. Then another 30 ml of 7M ammonia in MeOH was added and the mixture was stirred at 40 ° C overnight. NMR showed that the starting material disappeared completely. The solvent was removed and the residue was dissolved in 2N HCI and then lyophilized to provide 10.8 g of oil salt product, which was dissolved in MeOH - H2O at 0 ° C and the resin (AG1-X8, hydroxide form) was added in portions with stirring until the pH of the solution was above 9.0. After filtration, the filtrate was evaporated under reduced pressure to provide the free amine 1-amino-3-pyrrolidin-1-yl-propan-2-ol as a yellowish oil (8.6 g). This crude product was used for the reaction without further purification.

2. 4- [6-Amino- 5- (2,6-dichloro-benzyloxy) pyridin-3-yl] -N- (2

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175/470 hydroxy - 3-pyrrolidin-1-yl-propyl) -benzamide was prepared from 4- [6 amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid and 1-amino -3pyrrolidin-1-yl-propan-2-ol following procedure 4.

Examples I - 47 to I - 52:

[000300] The compounds of Examples 1-47 to 1-52 were prepared according to procedure 4 of 4- [6-amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -benzoic acid and : 3-fluoro-1- (2S) -pyrrolidin-2-ylmethylpiperidine (prepared according to the procedures for (R) - 2pyrrolidin-1-ylmethyl-pyrrolidine) (Example 1 - 47); 1-cyclopropyl-piperazine (Example 1-48); (R) - 2 - [(cyclopropylmethyl-amino) -methyl] -pyrrolidine (prepared according to the procedures for (R) - 2-pyrrolidin-1-ylmethylpyrrolidine) (first fraction, Example 1-49; second fraction, Example 1 - 50); N- (2-hydroxy-3-pyrrolidin-1-yl-propyl) -N-methyl amine (prepared according to the same procedure as 1-amino-3-pyrrolidin-1-ylpropan-2-ol (Example 1 - 51); and (2S) - 2 - [(3R) -3-hydroxy - pyrrolidin-1ylmethyl) -pyrrolidine (prepared according to the procedure for (R) -

2-pyrrolidin-1-ylmethyl-pyrrolidine) (Example 1 - 52).

Example I - 53:

[000301] 3- [6-Amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] benzoic acid was prepared from 5-bromo-3- (2,6-dichloro-benzyloxy) - pyridin-2ylamine and 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid following procedure 3.

Example I - 54:

[000302] {3- [6-Amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone was prepared from 3 [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -benzoic acid and (R) - 2pyrrolidin-1-ylmethyl-pyrrolidine following the procedure 4.

Example I - 55:

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1. To a solution of 4- (4,4,5,5-tetramethyl- [1,3] dioxolan-2yl) -phenol (10.0 g, 45.5 mmoles) and CS2CO3 (23.5 g, 68 , 25 mmoles) in DMF (60 ml) was added to ethyl-bromoacetate (11.6 g, 68.25 mmoles). The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate, washed with water, dried over Na2SO4. After filtration and evaporation, the residue was dried under high vacuum to provide [4- (4,4,5,5tetramethyl- [1,3] dioxolan-2-yl) -phenoxy] -acetic acid ethyl ester (12, 52 g, 90% yield) as an oil.

2. A mixture of 5-bromo-3- (2,6-dichloro-benzyloxy) -pyridin2-ylamine (Example I (a)) (2.2 g, 6.3 mmol), ethyl acid ester [4 (4,4,5,5-tetramethyl- [1,3] dioxolan-2-yl) -phenoxy] -acetic (2.9 g, 1.5 eq.), Bis (triphenylphosphine) palladium (II) chloride (136 mg) and sodium carbonate (1.93 g, 3.0 eq.) In ethylene glycol dimethyl ether (30 ml), DMF (5 ml) and water (8 ml) was heated to 90 - 100 ° C under nitrogen for 7 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on a silica column to produce {4 [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy acid ethyl ester }-acetic. This ester was treated with sodium carbonate and water at room temperature overnight. The reaction was diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on a silica column to produce 4- [6-amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] phenoxy} -acetic acid.

Example I - 56: [000303] 2- {4- [6-Amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 Petition 870190089642, of 10/09/2019 , p. 181/482

177/470 [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl] -ethanone was prepared from acid

4- [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic and (R) 2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I - 57:

[000304] 2- {4- [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 [(2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidin -1-yl] -ethanone was prepared from acid

4- [6-amino- 5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic and (S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I - 58:

[000305] 3- (2,6-Dichloro-benzyloxy) - 5- (1 H-indol-5-yl) -pyridin-2-ylamine was prepared from 5-bromo-3- (2,6-dichloro-benzyloxy ) -pyridin-2-ylamine and indole-5-boronic acid following procedure 3.

Example I - 59:

[000306] To a solution of 3- (2,6-Dichloro-benzyloxy) - 5- (1 H-indol-5yl) -pyridin-2-ylamine (Example 1 - 58, 200 mg, 0.52 mmol) in acetic acid (4 ml) and trifluoroacetic acid (1 ml) was added 1-methyl-4piperidone (0.32 ml, 2.6 mmoles). The solution was refluxed overnight, and evaporated. The residue was dissolved in ethyl acetate, washed with saturated NaHCOs and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95: 5: 0.1) to provide 3- (2,6-dichloro-benzyloxy) - 5- [3- (1 -methyl-1,2,3,6-tetrahydro-pyridin-4-yl) 1 H-indol-5-yl] -pyridin-2-ylamine (103.5 mg, 41% yield) as an orange crystalline solid .

Example I - 60:

[000307] To a degassed solution of 3- (2,6-dichloro-benzyloxy) -

5- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1 H-indol-5-yl] -pyridin-2ylamine (example I - 61, 130 mg, 0 , 27 mmol) in methanol (50 ml) and acetic acid (5 ml) 10% Pd / C (50 mg) was added. The solution was degassed and charged with hydrogen three times, and in

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178/470 was then stirred under a hydrogen test flask overnight. The mixture was filtered through a pad of celite, washed with methanol, and then condensed. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95: 5: 0.1) to provide 3- (2,6-dichloro-benzyloxy) - 5- [3- (1 -methyl-piperidin-4-yl) 1 H-indol-5-yl] -pyridin-2-ylamine as a white solid.

Examples I - 61 - I - 68:

[000308] The compounds of Examples I - 61 to I - 68 were prepared according to procedure 5 of 3- (2,6-Dichloro-benzyloxy) - 5- (1 Hindol-5-yl) -pyridin- 2- ilamine e: morpholine (Example I - 61); piperidine (Example I - 62); pyrrolidine (Example I - 63); diethylamine (Example I -

64); pyrrolidin-3-yl-carbamic acid tert-butyl ester (Example I -

65); 2,6-dimethyl-morpholine followed (Example I - 66); (R) -pyrrolidin-3yl-acetamide (Example I - 67); and piperazin-1-yl-ethanone (Example I - 68). Example I - 69:

[000309] 3- (2-Chloro-3,6-difluoro-benzyloxy) - 5- (1 H-indol-5-yl) -pyridin-2ylamine was prepared from 5-bromo-3- (2-chloro-3 , 6-difluoro-benzyloxy) pyridin-2-ylamine and indole-5-boronic acid following the procedure

3.

Examples I - 70 to I - 75:

[000310] The compounds of Examples I - 70 to I - 75 were prepared according to procedure 5 of 3- (2-chloro-3,6-difluoro-benzyloxy) - 5 (1 H-indol-5-yl) -pyridin-2-ylamine and: piperazin-1-yl-ethanone (Example I 70); 2,6-dimethyl-morpholine (Example I - 71); (3S) -pyrrolidin-3-ylacetamide (Example I - 72); piperidine (Example I - 73); morpholine (Example I - 74); and pyrrolidine (Example I - 75).

Example I - 76:

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1. To a stirred solution of ethyl 5-bromo-1 H-indole-2-carboxylate (5 g, 18.6 mmol) in DMSO (75 mL, 0.25 M), 4.4.4 ', 4', 5.5,5 ', 5'-octamethyl- 2,2'-bI - 1,3,2-dioxaborolane (11.2 g, 44.3 mmoles), potassium acetate (5.5 g, 56.0 mmoles), and [bis (diphenylphosphino) ferrocene] dichloropalladium (II) (1.23 mmol) were added. The mixture was degassed and charged with nitrogen three times, and then heated to 80 ° C under nitrogen overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (2 x 100 ml). The mixture was washed with water (1 x 50 ml), brine (1 x 50 ml), dried over MgSO4, and purified on a silica gel column to yield 5- (4,4,5,5-tetramethyl-1, 3,2dioxaborolan-2-yl) -1 ethyl H-indole-2-carboxylate as a not entirely white solid. ^{1 H} NMR (400 MHz, DMSO-d6) δ 1.31 (t, 3 H), 4.32 (m, 2 H), 7.18 (s, 1 H), 7.42 (d, 1 H ), 7.54 (d, 1 H), 8.05 (s, 1 H), 11.96 (s, 1 H); MS m / z 315 (M + 1).

2. 5- [6-Amino-5- (2,6-dichloro-benzyloxy) -pyridin-3-yl] -1 H-indole-2-carboxylic acid ethyl ester was prepared from 5bromo-3- (2 , 6-dichloro-benzyloxy) -pyridin-2-ylamine and 5- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -1 H-indole ethyl ester - 2 carboxylic following procedure 3.

Example I - 77:

[000311] To a mixture of ethyl 5- {6-amino-5 - [(2,6-dichlorobenzyl) oxide] pyridin-3-yl} -1 H-indole-2-carboxylate (2.5 g, 5 , 5 mmoles) in methanol: water (60 ml: 20 ml), lithium hydroxide (0.65 g, 27.1 mmoles) was added. The reaction was heated to reflux overnight. Most

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180/470 of the solvent was evaporated and the mixture was acidified, and stirred for 10 minutes. The precipitate was filtered and washed with water to produce 5- {6-amino-5 - [(2,6-dichlorobenzyl) oxide] pyridin-3-yl} -1 H-indole-2-carboxylic acid as a tan solid.

Examples I - 78 to I - 85:

[000312] The compounds of Examples 1-78 to 1-85 were prepared according to procedure 4 of 5- [6-Amino-5- (2,6-dichlorobenzyloxy) -pyridin-3-yl] -1 H -indole-2-carboxylic and: N-methylpiperazine (Example I - 78); (3R) -3-dimethylamino-pyrrolidine (Example I - 79); (2R) -

2-pyrrolidin-1-ylmethyl-pyrrolidine (prepared as in example I - 39) (Example I - 80); 2-pyrrolidin-1-yl-ethylamine (Example I - 81); 2-morpholin-

4-yl-ethylamine (Example I - 82); (S) pyrrolidin-3-yl-carbamic acid tert-butyl ester (Example I -83), followed by deprotection of the Boc group in 20% trifluoroacetic acid in dichloromethane (Example I -84); 2-hydroxy - 3-pyrrolidin-1-yl-propylamine (Example I - 85).

Example I - 86:

[000313] 4- (6-Amino-5-benzyloxy - pyridin-3-yl) -phenol was prepared from

3-benzyloxy-5-bromo-pyridin-2-ylamine and 4- (4,4,5,5-tetramethyl-1,3-2dioxabordan-2-yl) phenol following procedure 3.

Example I - 87:

[000314] 3-Benzyloxy-5-phenyl-pyridin-2-ylamine was prepared from 3benzyloxy - 5-bromo-pyridin-2-ylamine and phenylboronic acid following procedure 3.

Example I - 88:

[000315] 3- (3-Methoxy-benzyloxy) - 5-phenyl-pyridin-2-ylamine was prepared according to procedure 6.

Example I - 89 to I - 105:

[000316] The compounds of Examples I - 89 to I - 105 were prepared according to procedure 6 of: 2-chloro-4-fluoro-benzylbromide (Example I - 89); 2-chlorobenzylbromide (Example I - 90); 2.5 Petition 870190089642, of 10/09/2019, p. 185/482

181/470 dichlorobenzylbromide (Example I -91); 2-chloro-5-trifluoromethyl benzylbromide (Example I - 92); 2,4-Dichloro-5-fluoro-benzylbromide (Example I - 93); 2-chloro-3-trifluoromethyl-benzylbromide (Example I -94); 2-chloro3,6difluoro-benzylbromide (Example I - 95); 3,4-dichloro-benzylbromide (Example I -96); 2-bromomethyl-benzonitrile (Example I -97); 2-chloro-6-fluoro-3-methyl-benzylbromide (Example I -98); 2-bromomethyl-1,3,4-trifluorbenzene (Example I - 99); 2-bromomethyl-1,3-difluoro-benzene (Example I - 100); 2-bromomethyl-1,3-difluor-4-methyl-benzene (Example I - 101); 2bromomethyl-4-chloro-1,3-difluoro-benzene (Example I - 102); 2bromomethyl-1-chloro-3-fluorobenzene (Example I - 103); 4-bromomethyl-2-fluoro-1-methoxy-benzene (Example I-104); and 1-bromomethyl-3-nitrobenzene, followed by the reduction of the nitro group to amino and reaction with methanesulfonyl chloride (Example I - 105).

Example I - 106:

[000317] 5- [4- (2-Morfolin-4-yl-ethoxy) -phenyl] -3- (3-nitro-benzyloxy) -pyridin2-ylamine was synthesized according to procedure 7.

Example I - 107 to I - 110:

[000318] The compounds of Examples I - 107 to I - 110 were prepared according to procedure 7 of: 1-bromomethyl-naphthalene (Example I - 107); 2-bromomethyl-3-chloro-1,4-difluoro-benzene (Example I -108); 2-bromo-N- (4-isopropyl-phenyl) - 2-phenyl-acetamide (Example I 109); and 3-bromomethyl-5-chloro-benzo [b] thiophene (Example I - 110). Example I - 111:

[000319] {4- [6-Amino- 5- (4-fluoro-2-trifluoromethyl-benzyloxy) -pyridin-3-yl] phenyl} - [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -il] -methanone was synthesized according to procedure 8.

Example I - 112 to I - 117:

[000320] The compounds of Examples I - 112 to I - 117 were prepared according to procedure 8 of: 2-bromomethyl-1-fluoro-3trifluoromethyl-benzene (Example I - 112); 2-bromomethyl-4-fluorine-1 Petition 870190089642, of 10/09/2019, p. 186/482

182/470 trifluoromethyl-benzene (Example I - 113); 1- (1-bromo-ethyl) - 2-trifluoromethyl-benzene (Example I - 114); 1-bromo-2-bromomethylbenzene (Example I - 115); 1-bromomethyl-3-fluor-2-trifluoromethylbenzene (Example I - 116); and 2-bromomethyl-3-chloro-1,4-difluoro-benzene (Example I - 117).

Example I - 118 to I - 121:

[000321] The compounds of Examples I - 118 to I - 121 were prepared according to procedure 3 of 5-bromo-3- (2,6-difluoro-benzyloxy) -pyridin-2-ylamine and: 4- (4.4 , 5,5-tetramethyl- [1,3] dioxolan-2-yl) phenol (Example I - 118); 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan2-yl) - phenoxy] -ethyl} -morpholine (Example I - 119); 4- (4,4,5,5-tetramethyl [1,3] dioxolan-2-yl) -1 H-indole (Example I -120); and 4- (4,4,5,5tetramethyl- [1,3] dioxolan-2-yl) -benzoic acid (Example I - 121).

Example I - 122:

[000322] {4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2R) 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone was prepared from 4 [6-amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid and (2R) - 2pyrrolidin-1-ylmethyl-pyrrolidine following the procedure 4.

Example I - 123:

[000323] {4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenyl} - [(2S) 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone was prepared from 4 [6-amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid and (2S) - 2pyrrolidin-1-ylmethyl-pyrrolidine following the procedure 4.

Example I - 124:

[000324] {4- [6-Amino- 5- (2,6-difluoro-benzyloxy) pyridin-3-yl] -phenoxy} -acetic acid ethyl ester was prepared from 5-bromo-3- (2, 6-diflúorbenzyloxy) -pyridin-2-ylamine and ethyl ester of [4- (4,4,5,5tetramethyl- [1,3] dioxolan-2-yl) -phenoxy] -acetic acid following the procedure 3.

Example I - 125:

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183/470 [000325] {4- [6-Amino-5- (2,6-difluoro-benzyloxy) pyridin-3-yl] -phenoxy} -acetic acid ethyl ester (1.0 g, 2.41 mmoles) was treated with sodium carbonate (1.28 g, 12.05 mmoles) and water (10 mL) at 90 - 100 ° C overnight. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on a silica column to produce 4- [6 amino-5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy) -acetic acid.

Example I - 126:

[000326] 2- {4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin -1-yl] -ethanone was prepared from acid

4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic and (2R) 2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I - 127:

[000327] 2- {4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -1 [(2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidin -1-yl] -ethanone was prepared from acid

4- [6-Amino- 5- (2,6-difluoro-benzyloxy) -pyridin-3-yl] -phenoxy} -acetic and (2S) 2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Examples I - 128 to I - 134:

[000328] The compounds of Examples I - 128 to I - 134 were prepared according to procedure 3 of 4- (4,4,5,5-tetramethyl [1,3] dioxolan-2-yl) -phenol and: 5-bromo-3- (2-chloro-6-fluoro-benzyloxy) -pyridin2-ylamine (Example I-128); 5-bromo-3- (2-chloro-4-fluoro-benzyloxy) pyridin-2-ylamine (Example I - 129); 5-bromo-3- (2,4-dichloro-benzyloxy) pyridin-2-ylamine (Example I -130); 2- (2-amino-5-bromo-pyridin-3yloxymethyl) -benzonitrile (Example I - 131); 5-bromo-3- (2-trifluoromethylbenzyloxy) -pyridin-2-ylamine (Example I - 132); 5-bromo-3- (2-chlorobenzyloxy) -pyridin-2-ylamine (Example I -133); and 5-bromo-3- (4-tert-butylbenzyloxy) -pyridin-2-ylamine (Example I - 134).

Example I - 135:

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1. To a solution of 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-

2-yl) -phenylamine (5.00 g, 22.8 mmoles) in methylene chloride (100 ml) and

4-methylmorpholine (16 ml) at 0 ° C methanesulfonyl chloride (2.1 ml, 28 mmol) was added. The mixture was stirred at room temperature for 2 hours, and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide N- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] - methanesulfonamide as a white solid (6.32 g, 93% yield). MS m / z 298 (M + 1).

2. N- {4- [6-Amino- 5- (2-cyano-benzyloxy) -pyridin-3-yl] -phenyl} - methanesulfonamide was prepared following procedure 3 of 2- (2-Amino-5 -bromo-pyridin-3-yloxymethyl) -benzonitrile and N- [4- (4,4,5,5tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -methanesulfonamide. Example I - 136:

[000329] 10% NaOH solution (25 mL) was added to N- {4- [6 amino- 5- (2-cyano-benzyloxy) -pyridin-3-yl] -phenyl} -methanesulfonamide (Example I - 135 , 650 mg, 1.65 mmol) in ethylene glycol (55 ml). The mixture was heated to reflux and allowed to stir for 24 hours. The reaction was cooled to room temperature. Most of the solvent was evaporated and the mixture was acidified. The precipitated solid was filtered to produce 2- [2-Amino-5- (4-methanesulfonylamino-phenyl) -pyridin-3yloxymethyl] -benzoic acid as a light brown solid. The filtrate was neutralized and extracted with EtOAc (5 x 20 ml). The organic layer was combined, dried over MgSO4, and concentrated to produce 2- [2-Amino-5 (4-methanesulfonylamino-phenyl) -pyridin-3-yloxymethyl] -benzamide as a not entirely white solid.

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Example I - 137:

[000330] 2- [2-Amino-5- (4-methanesulfonylamino-phenyl) -pyridin-3yloxymethyl] -benzoic acid was prepared as in Example I - 136.

Example I - 138 to I - 140:

[000331] The compounds of Examples I - 138 to I - 140 were prepared according to procedure 4 of 2- [2-amino-5- (4-methanesulfonylamino-phenyl) -pyridin-3-yloxymethyl] -benzoic acid and: N -methylpiperazine (Example I - 138); 2-hydroxyethylamine (Example I - 139); and isobutylamine (Example I - 140).

Example I - 141:

[000332] 5-Bromo-3- (2-chloro-6-fluor-benzyloxy) -pyridin-2-ylamine (Example I (e), 9.00 g, 27.0 mmoles), 4-carboxybenzenoboronic acid (4 , 41 g, 27.0 mmoles), tetracis (triphenylphosphine) palladium (0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95.0 mmoles), dimethylformamide (72 mL) and water (36 mL) were loaded into a 250 mL flask with a three-necked circular base equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 ° C to 98 ° C over a period of 4 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5) showed a sign of starting material at Rf 0.7, product at Rf 0.4 and some small impurities. The mixture was cooled to 45 ° C. The solids were collected by vacuum filtration, washed with 30 mL of 1: 1 ethanol: water and discarded. The filtrate was diluted with 432 ml of water and 8 ml of 9N potassium hydroxide solution (to pH 12 - 13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 ml of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 ml of ethanol: water 1: 1 and dried under vacuum. Petition 870190089642, of 10/09/2019, p. 190/482

186/470 cuo to provide 2.5 g of 4- [6-amino- 5- (2-chloro-6-fluorobenzyloxy) -pyridin-3-yl] -benzoic acid and a second compound as a brown solid in a ratio of about 1: 1 per ^{1 H} -NMR. This material was discarded. The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of 1: 1 ethanol: water and dried under vacuum to provide 3.6 g (36% yield) of 4 [6-amino-5- (2-chlorine) acid -6-fluoro-benzyloxy) -pyridin-3-yl] -benzoic as a brown solid containing 5-10% impurity per ^{1 H} -NMR. Examples I - 142 to I - 149:

[000333] The compounds of Examples I - 142 to I - 149) were prepared according to procedure 4 of 4- [6-amino-5- (2chloro-6-fluoro-benzyloxy) -pyridin-3-yl] -benzoic and: (2R) - 2-pyrrolidin-1ylmethyl-pyrrolidine (Example I - 142); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 143); (3S) -3-dimethylamino-pyrrolidine (Example I - 144); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I - 145); N-methylpiperazine (Example I - 146); 1-piperazin-1-ylethanone (Example I - 147); 2-morpholin-4-yl-ethylamine (Example I - 148);

3-morpholin-4-yl-propylamine (Example I - 149).

Example I - 150:

[000334] 5-Bromo-3- (2-chloro-benzyloxy) -pyridin-2-ylamine (4.50 g, 14.3 mmoles), 4-carboxybenzenoboronic acid (2.62 g, 15.8 mmoles), tetracis (triphenylphosphine) palladium (0) (0.56 g, 0.5 mmol), potassium carbonate (6.90 g, 50 mmol), dimethylformamide (36 mL), and water (18 mL) were loaded into a vial with a circular base of three 250 ml necks equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 82 to 93 ° C over a period of 4 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5)

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187/470 showed the product at Rf 0.3 and some small impurities. The mixture was cooled to 45 ° C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol: water 1: 1 and discarded. The combined filtrate was diluted with 216 ml of water and 4 ml of 9N potassium hydroxide solution (to pH 12 - 13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norite . The solids were collected by vacuum filtration through a celite pad and washed with 10 mL of water. The solids were discarded. The combined filtrate was cooled in an ice bath and acidified to pH 7 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 20 ml of ethanol: water 1: 1 and dried under vacuum to provide 2.7 g (53% yield) of 4- [6-amino-5- (2- chloro-benzyloxy-pyridin-3-yl] benzoic.

Examples I - 151 to I - 159:

[000335] The compounds of Examples I - 151 to I - 159 were prepared according to procedure 4 of 4- [6-amino-5- (2-chlorobenzyloxy) -pyridin-3-yl] -benzoic acid and: ( 2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 151); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-152); (3S) -3-dimethylamino-pyrrolidine (Example 1-153); pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1-154); 4pyrrolidin-1-yl-piperidine (Example 1-155); N-methylpiperazine (Example 1-156); 1-piperazin-1-yl-ethanone (Example I - 157); 2-morpholin-4-ylethylamine (Example 1-158); and 3-morpholin-4-yl-propylamine (Example 1 159).

Example I - 160:

[000336] 2- (2-Amino-5-bromo-pyridin-3-yloxymethyl) -benzonitrile (9.0 g,

29.6 mmoles), 4-carboxybenzenoboronic acid (5.4 g, 32.5 mmoles), tetracis (triphenylphosphine) palladium (0) (1.1 g, 1.0 mmol), potassium carbonate

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188/470 anhydrous sodium (13.8 g, 70.0 mmoles), dimethylformamide (72 mL) and water (36 mL) were loaded into a 250 ml three-necked circular flask equipped with a thermometer, a condenser reflux and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90 ° C over a period of 2 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5) showed a sign of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45 ° C. The sticky solids were collected by vacuum filtration, washed with 30 ml of ethanol: water 1: 1 and discarded. The filtrate was diluted with 432 ml of water and 8 ml of 9 N of potassium hydroxide solution (to pH 12 - 13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 ml of water. The solids were discarded. The filtrate was cooled in an ice bath, acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to provide 8.5 g (83% yield) of 4- [6-amino-5- (2-cyano-benzyloxy) -pyridin-3 acid -il] -benzoic acid as a very dark solid. Examples I - 161 to I - 170:

[000337] The compounds of Examples 1-161 to 1-170 were prepared according to procedure 4 of 4- [6-amino-5- (2-cyanobenzyloxy) -pyridin-3-yl] -benzoic acid and: ( 2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-161); (2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1 162); (3S) -3-dimethylamino-pyrrolidine (Example 1-163); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I 164); 4-pyrrolidin-1-yl-piperidine (Example 1-165); N-methylpiperazine (Example 1-166); 1-piperazin-1-yl-ethanone (Example I - 167); 1-methylpiperidin-4-ylamine (Example 1-168); 2-Morfolin-4-yl-ethylamine (Exem

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189/470 (1-169); and 3-morpholin-4-yl-propylamine (Example 1 -170).

Example I - 171:

[000338] 5-Bromo-3- (2,4-dichloro-benzyloxy) -pyridin-2-ylamine (6.96 g, 20.0 mmoles), 4-carboxybenzenoboronic acid (3.98 g, 24.0 mmoles ), tetracis (triphenylphosphine) -palladium (0) (0.74 g, 0.66 mmol), potassium carbonate (9.7 g, 70 mmoles), dimethylformamide (35 ml) and water (17 ml) were loaded into a 250 ml bottle with a three-necked circular base equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated to 81 to 95 ° C over a period of 9 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5) showed a sign of starting material at Rf 0.7, product at Rf 0.4 and impurities at Rf 0.5 and 0 , 3. The mixture was cooled to room temperature and allowed to rest for about 48 hours. The solids were collected by vacuum filtration, washed with 30 ml of ethanol: water 1: 1 and saved. The filtrate was diluted with 210 ml of water and 8 ml of 9 N of potassium hydroxide solution (to pH 12 13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 ml of water to provide about 1 g of a product mixture and staining of starting material. This mixture was discarded. The filtrate was cooled in an ice bath and acidified to pH 5 - 6 with about 10 ml of acetic acid. The solids were collected by vacuum filtration, washed with 10 mL of ethanol: water 1: 1 and dried under vacuum to provide 2.9 g (37% yield) of 4- [6 amino- 5- (2,4- dichloro-benzyloxy) -pyridin-3-yl] -benzoic as a brown solid.

Examples I - 172 to I - 181:

[000339] The compounds of Examples 1-172 to 1-181 were prepared according to procedure 4 of 4- [6-amino-5- acid (2.4 Petition 870190089642, of 10/09/2019, p. 194 / 482

190/470 dichloro-benzyloxy) -pyridin-3-yl] -benzoic and: (2R) - 2-pyrrolidin-1-ylmethylpyrrolidine (Example 1-172); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 173); (3S) -3-dimethylamino-pyrrolidine (Example 1-174);

(S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I - 175); 4-pyrrolidin-1-yl-piperidine (Example 1-176); Nmethylpiperazine (Example 1-177); 1-piperazin-1-yl-ethanone (Example 1-178); 1-methyl-piperidin-4-ylamine (Example 1-179); 2-morpholin-4-ylethylamine (Example 1-180); and 3-morpholin-4-yl-propylamine (Example 1181).

Example I - 182:

[000340] 5-Bromo-3- (2-trifluoromethyl-benzyloxy) -pyridin-2-ylamine (5.80 g, 16.7 mmol), 4-carboxybenzenoboronic acid (3.05 g, 18.4 mmol), tetracis (triphenylphosphine) -palladium (0) (0.62 g, 0.6 mmol), potassium carbonate (8.10 g, 58 mmoles), dimethylformamide (47 ml) and water (23 ml) were loaded into a vial 250 ml three-necked circular base equipped with a thermometer, reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 93 ° C over a period of 4 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5) showed the product at Rf 0.6 and some small impurities. The mixture was cooled to 45 ° C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol: water 1: 1 and discarded. The filtrate was diluted with 300 ml of water and 4 ml of 9 N potassium hydroxide solution (to pH 12 - 13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norite . The solids were collected by vacuum filtration through a Celita pad and washed with 10 mL of water. The solids were discarded. The filtrate was cooled in an ice bath and acidified to pH 7.3 with acetic acid using a pH meter. The solids were

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191/470 were collected by vacuum filtration, washed with 20 ml of ethanol: water 1: 1 and dried under vacuum to provide 4.5 g (69% of production) of 4- [6-amino-5- (2 -trifluoromethyl-benzyloxy) -pyridin-3-yl] -benzoic as a brown solid.

Examples I - 183 to I - 192:

[000341] The compounds of Examples 1-183 to 1-192 were prepared according to procedure 4 of 4- [6-amino-5- (2trifluoromethyl-benzyloxy) -pyridin-3-yl] -benzoic acid and: ( 2R) - 2-pyrrolidin-1ylmethyl-pyrrolidine (Example 1-183); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 184); (3S) -3-dimethylamino-pyrrolidine (Example 1-185);

pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1-186); 4-pyrrolidin-1-yl-piperidine (Example 1-187); Nmethylpiperazine (Example 1-188); 1-piperazin-1-yl-ethanone (Example 1-189); 1-methyl-piperidin-4-ylamine (Example 1 -190); 2-morpholin-4-ylethylamine (Example 1 -191); and 3-morpholin-4-yl-propylamine (Example I 192).

Example I - 193:

[000342] 2- (2-Amino-5-bromo-pyridin-3-yloxymethyl) -benzonitrile (9.0 g,

26.8 mmoles), 4-carboxybenzenoboronic acid (4.9 g, 30.0 mmoles), tetracis (triphenylphosphine) -palladium (0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13 , 1 g, 95 mmoles), dimethylformamide (72 ml), and water (36 ml) were loaded into a 250 ml three-necked circular flask equipped with a thermometer, reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 96 ° C over a period of 2 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid 4: 6: 0.5) showed a signal of starting material at Rf 0.8, product at Rf 0.5 and an impurity at Rf 0.4. The mixture was cooled to 45 ° C and filtered to remove the solids. The filtrate was diluted with

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432 ml of water and 8 ml of 9 N of potassium hydroxide solution (for pH 12 - 13), cooled in an ice bath and 4 g of Celite and 2 g of Norite were added. The solids were collected by vacuum filtration through 4 g of Celita, washed with 30 mL of 1: 1 ethanol: water and discarded. The filtrate was cooled in an ice bath and acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 ml of water and dried under vacuum to provide 8.1 g (80% yield) 4- [6-amino- 5- (4-tert-butyl-benzyloxy) acid -pyridin-3-yl] -benzoic as a dark solid.

Examples I - 194 to I - 201:

[000343] The compounds of Examples 1-194 to 1-201 were prepared according to procedure 4 of 4- [6-Amino-5- (4-tert-butyl-benzyloxy) -pyridin-3-yl] -benzoic acid : (2R) - 2-pyrrolidin-1-ylmethylpyrrolidine (Example 1-194); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-195); (3S) -3-dimethylamino-pyrrolidine (Example 1-196); Nmethylpiperazine (Example 1-197); 1-piperazin-1-yl-ethanone (Example 1 198); 1-methyl-piperidin-4-ylamine (Example 1 -199); 2-morpholin-4-ylethylamine (Example 1-200); and 3-morpholin-4-yl-propylamine (Example 1 201).

Example I - 202:

[000344] 5-Bromo-3- (2-chloro-4-fluoro-benzyloxy) -pyridin-2-ylamine (9.00 g, 27.0 mmoles), 4-carboxybenzeneboronic acid (4.41 g, 27, 0 mmoles), tetracis (triphenylphosphine) -palladium (0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36 mL) they were loaded into a 250 mL flask of circular base with three necks equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 98 ° C over a period of 4 hours. Thin layer chromatography (ethyl acetate: hexane: acetic acid)

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193/470 co 4: 6: 0.5) showed a sign of starting material at Rf 0.7, product at Rf 0.4 and some small impurities. The mixture was cooled to 45 ° C. The solids were collected by vacuum filtration, washed with 20 mL of ethanol: water 1: 1 and discarded. The filtrate was diluted with 432 ml of water and 8 ml of 9 N of potassium hydroxide solution (to pH 12 - 13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 ml of water to provide about 1 g of a mixture that was discarded. The filtrate was cooled in an ice bath and acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of 1: 1 ethanol: water and dried under vacuum to provide 3.6 g (36% yield) of 4- [6-amino- 5- (2- chloro-4-fluoro-benzyloxy) pyridin-3-yl] -benzoic as a brown solid.

Examples I - 203 to I - 210:

[000345] The compounds of Examples 1- 203 to 1- 210 were prepared according to procedure 4 of 4- [6-Amino-5- (2-chloro-acid)

4-fluoro-benzyloxy) -pyridin-3-yl] -benzoic and: (2R) - 2-pyrrolidin-1-ylmethylpyrrolidine (Example 1 - 203); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 204); (3S) -3-dimethylamino-pyrrolidine (Example 1 - 205); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I - 206); N-methylpiperazine (Example I - 207); 1-piperazin-1yl) -ethanone (Example 1 - 208); 2-morpholin-4-yl-ethylamine (Example I 209); and 3-morpholin-4-yl-propylamine (Example I - 210).

Example I - 211:

[000346] 4- [6-Amino-5- (2-chloro-3,6difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid methyl ester was prepared following procedure 3 of 5-bromine -3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2ylamine and 4-methoxycarbonylbenzenoboronic acid as a non-solid

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194/470 completely white at 55% production. ^{1 H} NMR (CDCI3, 300 MHz) δ 3.94 (s, 3 H), 4.79 (brs, 2 H), 5.29 - 5.30 (d, 2 H, J, 1.6), 7.06 - 7.19 (dt,

H, J, 4.1, 9.0), 7.2 - 7.26 (m, 1 H), 7.37 - 7.38 (d, 1 H, 1.8), 7.58 7, 61 (m, 2 H), 8.01 - 8.02 (d, 2 H, J, 1.8), 8.08 - 8.11 (m, 2 H).

[000347] To a stirred solution of 4- [6 amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid methyl ester (2.5 g, 6 mmoles ) in hot isopropanol (300 ml) H2O (100 ml) containing LiOH (0.74 g, 31 mol) was added. The reaction immediately turned orange and was allowed to stir at room temperature for 18 hours. The reaction was diluted with EtOAc (200 ml) and brine (50 ml). The organic was separated and the aqueous was extracted with EtOAc (2 x 50 ml). The organic layers were combined and washed with brine (2 x 25 mL), dried with Na2SO4 and concentrated to dryness in vacuo to produce 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) acid ) pyridin-3-yl] -benzoic acid (2.4 g, 6 mmol, 99%) as a not entirely white solid.

Examples I - 212 to I - 224:

[000348] The compounds of Examples 1- 212 to 1- 224 were prepared according to procedure 4 of 4- [6-amino-5- (2-chloro-acid) 4-

3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic e: N-methylpiperazine (Example 1 - 212); 4-pyrrolidin-1-yl-piperidine (Example 1 - 213); piperidin-4-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1214); 3,5-dimethyl-piperazine (Example 1- 215); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1 - 216); (3S) -3-dimethylamino-pyrrolidine (Example I - 217); (R) -pyrrolidin-3-ylcarbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1 - 218); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1 - 219); 1

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195/470 methyl-piperidin-4-ylamine (Example I - 220); 2-pyrrolidin-1-yl-ethylamine (Example 1 - 221); 3-pyrrolidin-1-yl-propylamine (Example I - 222); 2morpholin-4-yl-ethylamine (Example 1 - 223); and 3-morpholin-4-yl-propylamine (Example 1-224).

Example I - 225:

[000349] 3- [6-Amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin- acid

3-yl] -benzoic acid was prepared using the same procedure as 5- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] benzoic acid bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-ylamine and 3-methoxycarbonylbenzenoboronic acid.

Examples I - 226 to I - 239:

[000350] The compounds of Examples 1- 226 to 1- 239 were prepared according to procedure 4 of 3- [6-amino-5- (2-chloro-acid)

3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid and: N-methylpiperazine (Example 1 - 226); 4-pyrrolidin-1-yl-piperidine (Example 1 - 227); piperidin-4-yl-carbamic acid tert-butyl ester, and then followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1 - 228); 3,5-dimethyl-piperazine (Example 1 - 229); (2S) - 2pyrrolidin-1-ylmethyl-pyrrolidine (Example 1- 230); (3S) -3-dimethylamino-pyrrolidine (Example 1 - 231); (R) -pyrrolidin- acid tert-butyl ester

3-yl-carbamic, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example 1-232); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I 233); 1-methyl-piperidin-4-ylamine (Example 1-234); 2-pyrrolidin-1-ylethylamine (Example 1 - 235); 3-pyrrolidin-1-yl-propylamine (Example 1,236); 2-morpholin-4-yl-ethylamine (Example I - 237); 3-morpholin-4-ylpropylamine (Example 1 - 238); and 1- [4- (2-amino-ethyl) -piperazin-1-yl] -ethanone (Example I - 239).

Example I - 240:

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1. 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (5 g,

22.8 mmoles) was dissolved in DCM (100 ml, 0.2 M), triethylamine (15 ml, 5.0 molar equivalent) was added to the mixture. The reaction was stirred at 0 ° C for 5 minutes. 3-Chloropropane-1-sulfonyl chloride (4.2 g, 23.0 mmol) was added in portions. The reaction was stirred at 0 ° C for 1 hour and gradually brought to room temperature, heated to reflux at 70 ° C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified through a silica column to produce 2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl) phenyl] isothiazolidine 1,1-dioxide as a solid not entirely white (5.2 g, 70% yield). ^{1 H} NMR (400 MHz, DMSO-d6) δ 7.62 (d, 2 H), 7.18 (d, 2 H), 3.76 (t, 2 H), 3.53 (t, 2 H ), 2.41 (t, 2 H), 1.28 (s, 12 H).

2. 3- (2-Chloro-3,6-difluoro-benzyloxy) - 5- [4- (1,1-dioxo-1X ^p - isothiazolidin-2-yl) -phenyl] -pyridin-2-ylamine was prepared following procedure 3 of 5-bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-amine and 2- [4- (4,4,5,5-1,1-dioxide) -tetramethyl-1,3,2-dioxaborolan-2yl) phenyl] isothiazolidine.

Example I - 241:

[000351] 3- (2,6-Dichloro-benzyloxy) - 5- [4- (1,1-dioxo-1X ^p -isothiazolidin-2yl) -phenyl] -pyridin-2-ylamine was prepared following the procedure 3 of 5-bromo-3- (2,6-dichloro-benzyloxy) -pyridin-2-amine and 2- [4- (4,4,5,5-tetramethyl-1,3-1,1-dioxide), 2-dioxaborolan-2-yl) phenyl] iso-thiazolidine.

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Example I - 242:

[000352] 5- [4- (1,1-dioxo-1X ^p -isothiazolidin-2-yl) -phenyl] -3- (2-fluor-6trifluoromethyl-benzyloxy) -pyridin-2-ylamine was prepared according to procedure 8.

Example I - 243:

[000353] {4- [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] phenyl}-2-Diethylamino-ethanesulfonic acid amide was synthesized according to procedure 9.

Examples I - 244 to I - 266:

[000354] The compounds of Examples 1-244 to 1-266 were prepared following procedure 9.

Examples I - 267 to I - 269:

[000355] The compounds of Examples 1- 267 to 1- 269 were prepared according to procedure 3, with purification by preparative reverse phase HPLC eluting with acetonitrile - water trifluoroacetic acid system and obtained as salts of trifluoroacetic acid, of

5-bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-ylamine and: 2 (dimethylaminomethyl) -phenylboronic acid (Example 1 - 267); 3- (pyrrolidin1-yl) -phenylboronic acid (Example 1- 268) and N- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] - methanesulfonamide (Example 1- 269). Example I - 270:

[000356] 5- [6-Amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin- acid

3-yl] -thiophene-2-carboxylic acid was prepared following procedure 3 starting from 5-bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-2-ylamine and 5-carboxythiophene acid - 2-boronic.

Examples I - 271 to I - 276:

[000357] Examples 1- 271 to 1- 276 were prepared according to procedure 4 of 5- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] - thiophene-2-carboxylic and: N-methylpiperazine (Example 1- 271); (2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1 Petition 870190089642, of 10/09/2019, page 202/482

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272); 1-methyl-piperidin-4-yl) -amine (Example I - 273); 3,5-dimethylpiperazine (Example I - 274); 2-pyrrolidin-1-yl-ethylamine (Example 1,275); and 4-pyrrolidin-1-yl-piperidine (Example I - 276).

Example I - 277:

[000358] 4- [6-Amino- 5- (3-fluoro-2-trifluoromethyl-benzyloxy) pyridin-3-yl] -benzoic acid was prepared using the same procedure as 4- [6-amino - 5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] - 5-bromo-3- (3-fluoro-2-trifluoromethyl-benzyloxy) pyridin-2-ylamino benzoic acid 4 -methoxycarbonylbenzenoboronic.

Examples I - 278 to I - 285:

[000359] Examples 1- 278 to 1- 285 were prepared according to procedure 4 of 4- [6-amino-5- (3-fluoro-2-trifluoromethylbenzyloxy) -pyridin-3-yl] -benzoic acid and : 4-pyrrolidin-1-yl-piperidine (Example 1 - 278); 1-methyl-piperidin-4-ylamine (Example 1- 279); 3,5-dimethylpiperazine (Example I - 280); 3-dimethylamino-pyrrolidine (Example 1281); (2S) - 2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I - 282); 2-morpholin-

4-yl-ethylamine (Example I - 283); N-methylpiperazine (Example I - 284); and

4-acetyl-piperazin-1-yl) -ethylamine (Example I - 285).

Examples I - 286 to I - 289:

[000360] The compounds of Examples I - 286 to I - 289 were prepared following procedure 9.

Example I - 290:

[000361] 4- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -benzoic acid was prepared using the same procedure as 4- [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -benzoic acid 5-bromo-3- [1- (2,6-dichloro-3 -fluor-phenyl) -ethoxy] pyridin-2-ylamine and 4-methoxycarbonylbenzenoboronic acid.

Examples I - 291 to I - 296:

[000362] The compounds of Examples 1- 291 to 1- 296 were prepared according to procedure 4 of 4- {6-amino- 5- [1- (2,6 Petition 870190089642, from 10/09/2019, p. 203/482

199/470 dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} -benzoic acid and: (2R) - 2-pyrrolidin-1ylmethyl-pyrrolidine (Example I - 291); 1-methyl-piperidin-4-ylamine (Example I - 292); (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example I - 293); 4-pyrrolidin-1-yl-piperidine (Example I 294); N-methyl-piperazine (Example 1 - 295); and 3,5-dimethyl-piperazine (Example I - 296).

Examples I - 297 to I - 299:

[000363] The compounds of Examples 1-297 to 1- 299 were prepared following procedure 9.

Examples I - 300 to I - 661 [000364] They were prepared according to the procedures referenced in the attached Tables, except when specifically described in the following paragraphs. When multiple procedures are referenced in the Tables separated by /, the indicated procedures were performed sequentially.

Example I - 311:

[000365] 3- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -benzoic acid was prepared using the same procedure as 4- [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -benzoic acid 5-bromo-3- [I - (2,6-dichloro-3 -fluor-phenyl) -ethoxy] pyridin-2-ylamine and 3-methoxycarbonylbenzenoboronic.

Example I - 312:

[000366] 3- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - (4-methyl-piperazin-1- il) -methanone was prepared following procedure 4 starting from 3- {6-amino- 5- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin-3-yl} -benzoic acid and 1-methyl-piperidin-4-ylamine.

Example I - 330:

[000367] 4- {6-Amino- 5- [1- (chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -benzoic acid was prepared using the same procedurePetition 870190089642, of 10/09/2019, p. 204/482

200/470 ment as 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -benzoic acid 5-bromo-3- [1- (2-chloro -3,6-difluoro-phenyl) -ethoxy] pyridin-2-ylamine and 4-methoxycarbonylbenzenoboronic.

Example I - 331:

[000368] 4- {6-Amino- 5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} N- (2-morpholin-4-yl-ethyl ) -benzamide was prepared following procedure 4 starting from 4- {6-amino- 5- [1- (2-chloro-3,6-difluoro-phenyl) ethoxy] -pyridin-3-yl} -benzoic acid and the corresponding amine.

Example I - 342:

[000369] 3- {6-Amino- 5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] pyridin-3-yl} -benzoic acid was prepared using the same procedure as 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) pyridin-3-yl] -benzoic acid 5-bromo-3- [1- (2-chloro-3,6 -difluoro-phenyl) -ethoxy] pyridin-2-ylamine and 3-methoxycarbonylbenzenoboronic acid.

Example I - 343:

[000370] (3- {6-Amino- 5- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyridin-3-yl} phenyl) - ((3R, 5S) -3 , 5-dimethyl-piperazin-1-yl) -methanone was prepared following procedure 4 starting with 3- {6-amino-5- [1- (2chloro-3,6-difluoro-phenyl) -ethoxy] acid -pyridin-3-yl} -benzoic acid and the corresponding amine.

Example I - 359:

1. Preparation of 2-hydroxy - 7-oxa-4-azonia-spiro [3,5] nonane: To a solution of morpholine (17.4 mL, 0.2 mol, 1.0 eq.) In ethanol (20mL ) epichlorohydrin (16.1 ml, 1.03 eq.) from the addition funnel was added. The reaction was cooled with an ice water bath and gradually raised to room temperature. After 24 hours, the reaction was concentrated at 50 ° C until no more distillate could be condensed. The resulting oil was stored at room temperature for 24 - 48 hours or until a significant mass of crystals was observed. The suspension was diluted with acetone and filtered. The solids were dried under high vacuum. This is

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201/470 provided 20 g of crystalline product. The mother liquids can be concentrated and the crystallization process repeated in increasing recovery.

2. Preparation of 1-Morfolin-4-yl-3- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] -propan-2-ol : 4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (440 mg, 2 mmol) was added to a stirred NaH suspension (96 mg, 2 eq ) in DMF (10 ml) at 0 ° C.

After 1 hour, 2-hydroxy-7-oxa-4-azonia-spiro [3.5] nonane (714 mg, 2 eq.) Was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated NH4Cl solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4 and condensed to dryness. The crude product was purified with a silica gel column eluting with 2% methanol in methylene chloride to produce 220 mg of product as a pink solid (30%). ^{1 H} NMR (400 MHz, DMSO-d6): δ

7.58 (d, J = 8.2 Hz, 2 H), 6.915 (d, J = 7.8 Hz, 2 H), 4.89 (d, J = 2.0 Hz, 1 H), 3 , 98 (m, 3 H), 3.55 (m, 4 H), 2.40 (m, 6 H), 1.27 (s, 12 H). MS (m / e): 364 [M + H] ⁺ (100%).

3. 1 - (4- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-

3-yl} -phenoxy) -3-morpholin-4-yl-propan-2-ol was prepared following the

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202/470 procedure 3 starting from 5-bromo-3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-2-ylamine and 1-morpholin-4-yl-3- [4 - (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] -propan-2-ol.

Example I - 371:

[000371] 4-Methyl-piperazine (4- {6-amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3yl} -phenyl) -amide 1-carboxylic acid was prepared according to procedure 10.

Example I - 386:

[000372] 3- {6-Amino- 5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} benzoic acid was prepared using the same procedure as 4- 5bromo-3- [1- (2,6-dichloro-phenyl) -ethoxy] [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic] - pyridin-2-ylamine and 3-methoxycarbonylbenzenoboronic.

Example I - 387:

[000373] (3- {6-Amino- 5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -phenyl) ((3R, 5S) -3,5-dimethyl -piperazin-1-yl) -methanone was prepared following procedure 4 starting with 3- {6-amino- 5- [1- (2,6-dichlorophenyl) -ethoxy] -pyridin-3-yl} -benzoic acid and 3,5-dimethyl-piperazine.

Example 399:

[000374] 4- {6-Amino- 5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3yl} -benzoic acid was prepared using the same procedure as 4- [ 5-bromo-3- [1- (2,6-dichloro-phenyl) -ethoxy] 6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] benzoic pyridin-2-ylamine and 4-methoxycarbonylbenzenoboronic acid.

Example 400:

[000375] 4- {6-Amino- 5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-3-yl} -N- (2pyrrolidin-1-yl-ethyl) -benzamide was prepared following procedure 4 starting from 4- {6-amino- 5- [1- (2,6-dichloro-phenyl) -ethoxy] -pyridin-

3-yl} -benzoic and 2-pyrrolidin-1-yl-ethylamine.

Example I - 454:

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203/470

[000376] To a solution of 5-bromo-3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] -pyridin-2-ylamine (5.00 g, 13.15 mmol) in DMF (73 mL) and water (1 mL) were added Zn (CN) 2 (4.50 g, 26.3 mmoles), Pd2 (dba) 3 (0.602 g, 0.65 mmol), and DPPF (0.86 g, 1.55 mmol). The mixture was degassed and charged with nitrogen three times, and then stirred under nitrogen at 100 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with a solution of saturated concentrated NH4Cl, NH4OH-water (4: 1: 4), then dried over MgSO4. The crude product was purified on a silica gel column eluting with ethyl acetate - hexanes (1: 4) to provide 6-Amino-5- [1- (2,6-dichloro-3-Fluorine-phenyl) -ethoxy] nicotinonitrile as a white solid (4.15 g, 97% yield).

Example I - 455:

[000377] 6-Amino- 5- [1- (2,6-dichloro-3-cyano-phenyl) -ethoxy] -nicotinonitrile was obtained as a side product of the preparation of 6-Amino- 5- [1 (2, 6-dichloro-3-fluoro-phenyl) -ethoxy] -nicotinonitrile.

Example I - 456:

[000378] 5-Aminomethyl-3- [1 - (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-2ylamine was prepared by reducing 6-amino- 5- [1- (2, 6-dichloro-3-fluoro-phenyl) -ethoxy] -nicotinonitrile. To a solution of borane in THF (1.0 M, 16.8 mL, 16.8 mmoles) was added 6-amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] nicotinonitrile ( 785 mg, 2.41 mmoles) in anhydrous THF (8 mL) at 0 ° C under nitrogen. The reaction solution was stirred under nitrogen at 0 ° C for 5 hours, and then HCI solution (6N, 12 ml) was added slowly followed by the addition of water (12 ml) and methanol (80 ml). The mixture was stirred overnight. After the evaporation of the solvents, the residue was divided between dichloromethane and

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204/470 NaOH solution (1 N). The water layer was extracted three times, and the combined extracts were dried over MgSO4. After filtration, evaporation and high dry vacuum, a white solid product was obtained (750 mg, 94% yield).

Example I - 457:

[000379] (R) - 2-Pyrrolidin-1-ylmethyl {6-amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3ylmethyl} -amide pyrrolidine-1-carboxylic acid was prepared with the same procedure as in step 4 in procedure 11.

Example I - 462:

[000380] (S) -1- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-

3-yl} -ethane-1,2-diol was prepared as follows: To an asymmetric dihydroxylation solution - α mixture (2.33 g) in a 1: 1 mixture of t-BuOH and water (8 mL of each ) cooled to 0 ° C, 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5-vinyl-pyridin-2-ylamine (500 mg, 1.67 mmol) was added. The reaction mixture was stirred at 0 ° C until consumption of the starting material. Three more charges of AD mixture were added periodically to increase the reaction rate. Water was added (5 ml) and the mixture was extracted with EtOAc (3 x 20 ml). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to provide (S) -1- {6 amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-3-yl} - ethane-1,2-diol (320 mg, 53% yield).

Example I - 463:

[000381] (R) -1- {6-Amino- 5- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyridin-

3-yl} -ethane-1,2-diol was prepared with the same procedure as Example I - 462 with α mixture of AD.

Examples II - 1 to II - 6:

[000382] The compounds of Examples II - 1 to II - 6 were prepared according to the Suzuki 3 coupling procedure of 5-bromoPetition 870190089642, of 10/09/2019, pg. 209/482

205/470

3- (2,6-dichloro-benzyloxy) -pyrazin-2-ylamine and: 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (Example II - 1); 2- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] isothiazolidine 1,1-dioxide (Example II - 2); 3- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] ethyl} -morpholine (Example II - 3); 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] -ethyl} -morpholine (Example II - 4); 4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenylamine (Example II - 5); and 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid (Example II - 6).

Example II - 7:

[000383] {4- [5-Amino-6- (2,6-dichloro-benzyloxy) -pyrazin-2-yl] -phenyl} [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl ] -methanone was prepared following the 4- [5-amino-6- (2,6dichloro-benzyloxy) -pyrazin-2-yl] -benzoic acid amidation procedure 4 and (2R) - 2-pyrrolidnI - 1-ylmethylpyrrolidine .

Example II - 8:

[000384] {4- [5-Amino-6- (2,6-dichloro-benzyloxy) -pyrazin-2-yl] -phenyl} - (4pyrrolidin-1-yl-piperidin-1-yl) -methanone was prepared following the 4- [5-amino-6- (2,6-dichloro-benzyloxy) pyrazin-2-yl] -benzoic acid and 4-pyrrolidin-1-yl-piperidine amidation procedure 4.

Examples II - 9 to II - 32:

[000385] The compounds of Examples II - 9 to 11-32 were prepared following the Suzuki 3 coupling procedure of 5-bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-ylamine and the following compounds prepared according to the procedure in Example 1- 243: 2morfolin-4- [4 (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide ilethanesulfonic (Example II - 9); 2-Piperidin-1-ylethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (Example II - 10); 2- (4-hydroxy - piperidin-1- acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide

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206/470 yl) -ethanesulfonic (Example II - 11); 2-Pyrrolidin-1-ylethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (Example II - 12); [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide of acid 2 - [(3R) -3-HydroxyI - pyrrolidin-1-yl ] ethanesulfonic (Example II - 13); 2 - [(2S) - 2-hydroxymethylpyrrolidin-1-yl [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide ethanesulfonic (Example II - 14); 2- (cyclopropylmethylamino) -ethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -ethanesulfonic acid (Example II - 15); 2-Dimethylaminoethanesulfonic acid [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (Example II - 16); 2-diethylaminoethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (Example II - 17); [4- (4,4,5,5-tetramethyl- [1,3,

2] dioxaborolan-2-yl) -phenyl] - 2- (4-acetyl-piperazin-1-yl) ethanesulfonic acid amide (Example II - 18); 2- [4- (2-hydroxy-acetyl) piperazin-1- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide il] -ethanesulfonic (Example II - 19); [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide 2-cyclopropylaminoethanesulfonic acid (Example II - 20); 2 - [(3R) - 2-hydroxymethylpyrrolidin-1-yl [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- 2-yl) -phenyl] -amide ethanesulfonic (Example II - 21); 2- (4-HydroxI - piperidine- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- 2-yl) -phenyl] -amide

1-yl) -ethanesulfonic (Example II [1,3,2] dioxaborolan-2-yl) -phenyl] -amide of yl) -ethanesulfonic (Example II [1,3,2] dioxaborolan-2-yl) -phenyl ] -ethanesulfonic amide (Example II [1,3,2] dioxaborolan-2-yl) -phenyl] -amide ethanesulfonic (Example II [1,3,2] dioxaborolan-2-yl) -phenyl] -amide

22);

acid

23);

in

24); in

25);

of [3- (4,4,5,5-tetramethyl2- (4-acetyl-piperazin-1 [3- (4,4,5,5-tetramethyl acid 2-piperidin-1-yl [3- (4.4 , 5,5-tetramethyl acid 2-diethylamino [3- (4,4,5,5-tetramethyl acid 2-morpholin-4-ylPetition 870190089642, of 10/09/2019, p. 211/482

207/470 ethanesulfonic (Example II [1,3,2] dioxaborolan-2-yl) -phenyl] -amide ethanesulfonic (Example II [1,3,2] dioxaborolan-2-yl) -phenyl] -amide ethanesulfonic (Example II26);

in

27);

in

28);

[3- (4,4,5,5-tetramethyl acid 2-pyrrolidin-1-yl [3- (4,4,5,5-tetramethyl acid 2-dimethylamino [3- (4,4,5,5-tetramethyl- [1.3.2] 2- [4- (2-hydroxy - acetyl) piperazin-1-yl] -ethanesulfonic acid dioxaboraolan-2-yl) -phenyl] -ethanesulfonic acid [Example II (cyclopropylmethyl-amino) -ethanesulfonic acid [ 1.3.2] dioxaborolan-2-yl) -phenyl] -amide (Example tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide

29); acid 2 [3- (4,4,5,5-tetramethylII - 30); [3- (4,4,5,5de 2 - [(3R) -3hydroxy - pyrrolidin-1-yl] -ethanesulfonic acid (Example II - 31); and [3- (4,4,5,5tetramethyl- [ 1,3,2] dioxaborolan-2-yl) -phenyl] -amide of 2-cyclopropylamino-ethanesulfonic acid (Example II - 32).

Example II - 33:

[000386] 4- [5-Amino-6- (2-chloro-3,6-diffuoro-benzyloxy) -pyrazin2-yl] -benzoic acid was prepared following the Suzuki 3 coupling procedure of 5-bromo-3- ( 2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-ylamine and 4- (4,4,5,5-tetramethyl-11,3,2] dioxa-borolan-2-yl) -benzoic acid.

Example II - 34:

[000387] {4- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] phenyl {- [(2R) - 2-pyrrolidin-1-ylmethyl-pyrrolidin -1-yl] -methanone was prepared following the 4- [5-amino-6- (2chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -benzoic acid amidation procedure 4 (2R) - 2-pyrrolidin-1ylmethyl-pyrrolidine.

Examples II - 35 to II - 46:

[000388] The compounds of Examples II - 35 to II - 46 were prepared according to the 4- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin- 2 amidation procedure 4 -yl] -benzoic and: 2pyrrolidin-1-yl-ethylamine (Example II - 35); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by Boc group deprotection

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208/470 with trifluoroacetic acid in dichloromethane (Example II - 36); 1- [4- (2 amino- ethyl) -piperazin-1-yl] -ethanone (Example II - 37); 3-pyrrolidin-1-ylpropylamine (Example 11-38); (3S) -3-dimethylamino-pyrrolidine (Example II - 39); (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example II - 40); 3,5-dimethyl-piperazine (Example II - 41);

4-pyrrolidin-1-yl-piperidine (Example II - 42); 3-morpholin-4-yl-propylamine (Example II - 43); 1-methyl-piperidin-4-ylamine (Example II - 44); 2-morpholin-4-yl-ethylamine (Example II - 45); and N-methylpiperazine (Example II - 46).

Example II - 47:

[000389] 3- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -benzoic acid was prepared following the Suzuki 3 coupling procedure of 5-bromo-3- ( 2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-ylamine (Example II (b)) and 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- 2 acid -il) benzoic (Aldrich, Milwaukee).

Examples II - 48 to II - 60:

[000390] The compounds of Examples II - 48 to II - 60 were prepared according to the 3- [5 amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin- 2 amidation procedure 4 -yl] -benzoic e: Nmethylpiperazine (Example II - 48); (R) pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example II - 49); (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example II - 50); 3,5-dimethyl-piperazine (Example II - 51); 3-morpholin-4-ylpropylamine (Example II - 52); 4-pyrrolidin-1-yl-piperidine (Example II 53); (3S) -3-dimethylamino-pyrrolidine (Example II - 54); 2-pyrrolidin-1-ylethylamine (Example II - 55); 1-methyl-piperidin-4-ylamine (Example II - 56); (2S) - pyrrolidin-1-ylmethyl-pyrrolidine (Example II - 57); 2-morfolin-4-yl

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209/470 ethylamine (Example II - 58); 2- (4-acetyl-piperazin-1-yl) -ethylamine (Example II - 59); and 3-pyrrolidin-1-yl-propylamine (Example II - 60).

Example II - 61:

[000391] 3- (2-Chloro-3,6-difluoro-benzyloxy) - 5- (1 H-indol-5-yl) -pyrazin2-ylamine was prepared from 5-bromo-3- (2-chloro-3 , 6-difluoro-benzyloxy) pyrazin-2-ylamine and indole-5-boronic acid following procedure 3.

Examples II - 62 to II - 68:

[000392] The compounds of Examples II - 62 to II - 68 were prepared according to procedure 5 of 3- (2-chloro-3,6-difluoro-benzyloxy) - 5- (1 H-indol-5-yl) - pyrazin-2-ylamine and: pyrrolidine (Example II

- 62); diethylamine (Example II - 63); 1-piperazin-1-yl-ethanone (Example II

- 64); 2,6-dimethyl-morpholine (Example II - 65); N- (S) -pyrrolidin-3-yl-acetamide (Example II - 66); piperidine (Example II - 67); and morpholine (Example II - 68).

Example II - 69:

[000393] 3- [1- (2-Chloro-3,6-difluoro-phenyl) - 2-methyl-propoxy] - 5- [4- (2morpholin-4-yl-ethoxy) -phenyl] -pyrazin- 2 -ylamine was prepared following the Suzuki 3 coupling procedure of 5-bromo-3- [1- (2-chloro-3,6difluoro-phenyl) - 2-methyl-propoxy] -pyrazin-2-ylamine and 4- {2 - [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] -ethyl} -morpholine.

Example II - 70:

[000394] (3- [1- (2-Chloro-3,6-difluoro-phenyl) -ethoxy] - 5- [4- (2-morpholin-4-ylethoxy) -phenyl] -pyrazin-2-ylamine, composed with trifluoro-acetic acid, was prepared following the Suzuki 3 coupling procedure of 5bromo-3- [1- (2-chloro-3,6-diflúor-phenyl) - 2-methyl-propoxy] -pyrazin-2-ylamine and 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxy] -ethyl} morpholine The product was purified with preparative HPLC C- 18 reverse phase eluting with acetonitrile-water-trifluoroacetic acid and obtained as a salt of trifluoroacetic acid.

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210/470

Examples II - 71 to II - 83:

[000395] The compounds of Examples II - 71 to II - 83 were prepared according to the Suzuki 3 coupling procedure of 5bromo-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - pyrazin-2-ylamine e: 4- {2- [4 (4,4,5,5-tetramethyl- [1,3, 2] dioxaborolan-2-yl) -phenoxy] -ethyl} -morpholine, followed by purification with a preparative C-18 reverse phase HPLC eluting with acetonitrile-water-trifluoroacetic acid obtained as a salt of trifluoroacetic acid (Example II - 71); N- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -methane-sulfonamide (Example II - 72); 2-pyrrolidin-1-yl-ethanesulfonic acid [4- (4, 4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (prepared as in Example I - 243) (Example II - 73); 2- (4-hydroxy - piperidin-1-yl) -ethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -ethanesulfonic acid (prepared as in Example I - 243) (Example II - 74); 2-Piperidin-1-ylethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (prepared according to the procedure in Example I - 243) (Example II - 75); 2- (cyclopropylmethyl-amino) -ethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dixoaborolan2-yl) -phenyl] -ethanesulfonic acid (prepared as in Example I - 243) (Example II - 76); [4- (4, 4, 5, 5tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenyl] -amide 2 - [(3R) -3hydroxy - pyrrolidin-1-yl] -ethanesulfonic acid ( prepared as in Example I 243) (Example II - 77); 2 - [(2S) - 2-hydroxymethyl-pyrrolidin-1-yl [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -amide] ethanesulfonic (prepared as in Example I - 243) (Example II - 78); [4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide of 2-dimethylamino-ethanesulfonic acid (prepared as in Example I - 243) (Example II - 79); 2-Morpholin-4-yl-ethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] (prepared as in Example I - 243 ) (Example II - 80); 2-Diethylamino acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide

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211/470 ethanesulfonic (prepared as in Example I - 243) (Example II - 81); 2-cyclopropylamino-ethanesulfonic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -amide (prepared as in Example I - 243); and 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid (Example II - 83).

Examples II - 84 to II - 88:

[000396] The compounds of Examples II - 84 to II - 88 were prepared according to the 3- {5 amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) - acid amidation procedure 4 ethoxy] -pyrazin-2-yl} -benzoic acid: (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example II - 84); (R) -pyrrolidin-3-ylcarbamic acid tert-butyl ester, followed by deprotection of the Boc group with trifluoroacetic acid in dichloromethane (Example II - 85); (2R) - 2-pyrrolidin-1-ylmethylpyrrolidine (Example II - 86); 2- (4-acetyl-piperazin-1-yl) -ethylamine (Example II - 87); and (2S) -pyrrolidin-1-ylmethyl-pyrrolidine (Example II - 88).

Example II - 89:

[000397] 3- {5-Amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin2-yl} -benzoic acid was prepared following the Suzuki 3 of 5 coupling procedure -bromo-3- [l- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2ylamine and 3- (4,4,5,5-tetramethyl- [1,3,2] acid dioxaborolan-2-yl) -benzoic. Example II - 90:

[000398] 3- {5-Amino-6- [1- 2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} N- (1-methyl-piperidin-4-yl) -benzamide was prepared following the 3- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin-2-yl} -benzoic acid amidation procedure 4 methyl-piperidin-4-ylamine.

Example II - 91:

[000399] 3- {5-Amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} N- (3-pyrrolidin-1-yl-propyl ) -benzamide was prepared following the 3- {5-amino-6- [1- (2,6-dichloro-3-fluorine acid) amidation procedure 4

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212/470 phenyl) -ethoxy] -pyrazin-2-yl} -benzoic and 3-pyrrolidin-1-yl-propylamine.

Example II - 92:

[000400] (3- {5-Amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2yl} -phenyl) - (4-pyrrolidin-1-yl- piperidin-1-yl) -methanone was prepared following the 3- {5-amino-6- [1- (2,6dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl acid amidation procedure 4 } -benzoic and 4-pyrrolidin-1-ylpiperidin-1-ylamine.

Example II - 93:

[000401] 4- [5-Amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin2-yl] -benzoic acid was prepared following the procedure following the 5-bromo-3- Suzuki 3 coupling procedure (3-fluoro-2-trifluoromethylbenzyloxy) -pyrazin-2-ylamine and 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid.

Example II - 94:

[000402] 4- [5-Amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] N- (2-morpholin-4-yl-ethyl) -benzamide was prepared following the procedure amidation 4 of 4- [5-amino-6- (3-fluoro-2-trifluoromethylbenzyloxy) -pyrazin-2-yl] -benzoic acid and 2-morpholin-4-yl-ethylamine.

Example II - 95:

[000403] 4- [5-Amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2-yl] N- (1-methyl-piperidin-4-yl) -benzamide was prepared following the procedure amidation 4 of 4- [5-amino-6- (3-fluoro-2-trifluoromethylbenzyloxy) -pyrazin-2-yl] -benzoic acid and 1-methyl-piperidin-4-ylamine acid.

Examples II - 96 to II - 211 [000404] They were prepared according to the procedures referenced in the enclosed Tables, except as specifically described in the following paragraphs.

Example II - 108:

[000405] 4- {5-Amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin2-yl} -benzoic acid was prepared using the same procedure as

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213/470 mo 4- [6-amino-5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] benzoic acid 5-bromo-3- [1- (2-chloro- 3,6-difluoro-phenyl) -ethoxy] -pyrazin-2ylamine and 4-methoxycarbonylbenzenoboronic acid.

Example II - 109:

[000406] 4- 5-Amino-6- [1- (2-chloro-3,6-difluoro-phenyl) -ethoxy] -pyrazin-2-yl} N- (3-pyrrolidin-1-yl-propyl) -benzamide was prepared following procedure 4 starting from 4- {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin- 2-yl} -benzoic acid and 3 -pyrrolidin-1-yl-propylamine.

Example II - 121:

[000407] 3- [5-Amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin2-yl] -benzoic acid using the same procedures as 4 [6-amino- 5- (2- 5bromo-3- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2-ylamine chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid and 3-methoxycarbonyl-benzene-boronic acid.

Example II - 122:

[000408] {3- 5-Amino-6- (3-fluoro-2-trifluoromethyl-benzyloxy) -pyrazin-2yl] -phenyl} - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone prepared following procedure 4 starting from 3- [5-amino-6- (3-fluoro-2trifluoromethyl-benzyloxy) -pyrazin-2-yl] -benzoic acid and 4-pyrrolidin-1-ylpiperidin-1-ylamine.

Example II - 145:

[000409] 4- {5-Amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin2-yl} -benzoic acid was prepared using the same procedure as acid 4- [6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] benzoic acid 5-bromo-3- [1- (2,6-dichloro-3-fluorine -phenyl) -ethoxy] -pyrazin- 2ylamine and 4-methoxycarbonylbenzenoboronic acid.

Example II - 148:

[000410] 4- {5-Amino-6- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin- 2-yl} N - ((R) - 2-hydroxy - 3 -pyrrolidin-1-yl-propyl) -benzamide was prepared following procedure 4 starting from 4- {5-amino-6- [1- (2,6

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214/470 dichloro-3-fluoro-phenyl) -ethoxy] -pyrazin-2-yl} -benzoic acid and (R) - 2-hydroxy - 3pyrrolidin-1-yl-propylamine.

Example II - 156:

[000411] 4- {5-Amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -irazin-2-yl} benzoic acid was prepared using the same procedure as 4- [ 5-bromo-3- [1- (2,6-dichloro-phenyl) -ethoxy] 6-amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] benzoic pyrazin-2-ylamine and 4-methoxycarbonylbenzenoboronic acid.

Example II - 157:

[000412] (4- {5-Amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -phenyl) (4-pyrrolidin-1-yl-piperidin-1 -yl) -methanone was prepared following procedure 4 starting from 4- {5-amino-6- [1- (2,6-dichloro-phenyl) ethoxy] -pyrazin- 2-yl} -benzoic acid and 4-pyrrolidin -1-yl-piperidin-1-ylamine.

Example II - 168:

[000413] 3- {5-Amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl) benzoic acid was prepared using the same procedure as 4- [6 5-bromo-3- [1- (2,6-dichloro-phenyl) -etoxy] -amino- 5- (2-chloro-3,6-difluoro-benzyloxy) -pyridin-3-yl] -benzoic acid - pyrazin-2-ylamine and 3-methoxycarbonylbenzenoboronic acid.

Example II - 169:

[000414] 3- {5-Amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] -pyrazin-2-yl} -N- (1 methyl-piperidin-4-yl) -benzamide was prepared following procedure 4 starting from 3- {5-amino-6- [1- (2,6-dichloro-phenyl) -ethoxy] pyrazin-2-yl} -benzoic acid and 1-methyl-piperidin-4 -ylamine.

Example II - 193:

[000415] 5- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2yl] -thiophene-2-carboxylic acid was prepared following procedure 3 starting with 5- bromo-3- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2ylamine and 5-carboxythophen-2-boronic.

Example II - 194:

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215/470 [000416] {5- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] thiophen-2-yl} - (4-methyl-piperazin- 1-yl) -methanone was prepared following procedure 4 starting with 5- [5-Amino-6- (2-chloro-3,6-difluoro-benzyloxy) -pyrazin-2-yl] -thiophene-2-carboxylic acid and 4-methyl-piperazin-1-amine.

Examples L-1 to L-176 [000417] were prepared according to procedure 40. In Table 5, the compounds are grouped into sections, with each section having a letter designation. Sample numbers are designated left and right by rows. For example, in Section A, the compounds in the top row, from left to right, are Examples L-1 to L-4, and the compounds in the second row are, from left to right, Examples L-5-L -8. % inhibition is the percentage of c-MET inhibition at 50 nM.

Examples L-177 to L-352 [000418] Were prepared according to procedure 41. In Table 6, compounds are grouped into sections, with each section having a letter designation. Sample numbers are designated from left to right by rows. % inhibition is the percentage of inhibition of c-MET at 1 pM.

Examples L-353 to L-548 [000419] Were prepared according to procedure 42. In Table 7, compounds are grouped into sections, with each section having a letter designation. Sample numbers are designated from left to right by rows. % inhibition is the percentage of inhibition of c-MET at 1 µM.

Examples L-549 to L-636 [000420] Were prepared according to procedure 43. In Table 8, compounds are grouped into sections, with each section having a letter designation. The example numbers are

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216/470 of those from left to right by rows. % inhibition is the percentage of c-MET at 1 μM.

BIOLOGICAL EXAMPLES [000421] It will be appreciated that, in any mentioned series of compounds, a range of biological activities will be observed. In its currently preferred aspects, this invention relates to novel compounds capable of modulating, regulating and / or inhibiting protein kinase activity. The following tests can be used to select those compounds demonstrating the ideal degree of the desired activity.

Assay Procedures [000422] The following in vitro assay can be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. A literature reference is provided (Technikova-Dobrova Z, Sardanelli AM, Papa S FEBS Lett. November 4, 1991; 292: 69-72).

[000423] The General Procedure is as follows: kinase test compounds and reagents are introduced into the test wells. The test is initiated by the addition of the enzyme kinase. Enzyme inhibitors reduce the measured activity of the enzyme.

[000424] In the continuous coupled spectrophotometric assay, the time-dependent production of ADP by the kinase is determined by analyzing the rate of consumption of NADH by assessing the decrease in absorbance at 340 nm. As PK produces ADP it is converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is subsequently converted to lactate by reaction with lactate dehydrogenase, which simultaneously converts NADH to NAD. NADH has an ab

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217/470 measurable sorbence at 340 nm, whereas NAD does not.

[000425] The currently preferred protocol for conducting continuous coupled spectrophotometric experiments for specific PKs is provided below. However, the adaptation of this protocol to determine the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.

Continuous HGFR Coupled Spectrophotometric Assay [000426] This assay analyzes the HGFR tyrosine kinase activity on the Met-2 substrate peptide, a peptide derived from the HGFR activation loop.

Materials and Reagents:

1. Upstate HGFR enzyme (Met, active) Cat. # 14- 526

2. Met-2 Peptide (HGFR Activation Loop) AcARDMYDKEYYSVHNK (MW = 1960). Dissolved in 200 mM HEPES, pH 7.5 to 10 mM raw material.

3. 1M PEP (phosphoenol-pyruvate) in 200 mM HEPES, pH

7.5

4. 100 mM NADH (BNicotinamide Adein Dinucleotide, Reduced Form) in 200 mM HEPES, pH 7.5.

5. 4 M MgCl2 (Magnesium Chloride) in ddH2O

6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5

7. 15 Units / mL LDH (Lactic Dehydrogenase)

8. 15 Units / mL PK (Pyruvate Kinase)

9. 5 M NaCl dissolved in ddH2O

10. Tween-20 (Protein Grade) 10% Solution

11. 1 M HEPES buffer: Sodium salt of (N- [2Hydroxyethyl] piperazine-N- [2-ethanesulfonic acid). Dissolve in ddH2O, adjust pH to 7.5, bring the volume to 1 L. Filter at 0.1 gm.

12. HPLC Grade Water; Burdick and Jackson # 365-4, 1X 4 li

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218/470 tros (or equivalent)

13. 100% DMSO (SIGMA)

14. Plates with half area of black flat base - Costar # 3880 for Ki and% inhibition determination.

15. 96-well polypropylene plates - Costar # 3359, circular base for serial dilutions.

16. UV-clear flat base plates - Costar # 3635 for% inhibition.

17. Beckman DU-650 w micro cell holders.

18. Beckman 4 position micro cell cuvette. Procedure:

[000427] Preparative Dilution Buffer (DB) for Enzyme (For 30 mL prep)

1. Final DB concentration is 2 mM DTT, 25 mM NaCl2, 5 mM MgCl2, 0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5.

2. Preparation of 50 mM HEPES by adding 1.5 ml of 1 M HEPES in 28.1 ml of ddH2O. Add the rest of the reagents. In a 50 mL conical flask, add 60 µL of 1M DTT, 150 µL of 5M NaCb, 150 µL of 1 M MgCb, and 30 µL of 10% Tween-20 to provide a total volume of 30 mL.

3. Vortex for 5 to 10 seconds.

4. Aliquot DB in 1mL / tube and label tubes as DB HGFR

5. Note: This can be prepared and stored ahead of time.

6. Freeze unused aliquots in microcentrifuge tubes in a freezer at - 20 ° C.

Prep Compounds.

1. For compound dilution plate, add 4 μL of 10

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219/470 mM of raw material in column 1 of plasca, and bring the volume to 100 µL with 100% DMSO.

2. Establish the Precision 2000 dilution method. A final concentration of 200 µM in 50% DMSO, 100 mM HEPES (1: 2 serial dilution).

Prep Coupled Enzyme Buffer :

1. Final test concentration:

[000428] Reagent (Raw Material Concentration) Final Test Concentration.

The. 1 mM PEP (1M)

B. NADH (100 mM) 300 µM

ç. 20 mM MgCl2 (4 M)

d. 2 mM DTT (1M)

and. ATP (500 mM) 300 uM

f. 200 mM HEPES (pH 7.5) 100 mM

g. Pyruvate Kinase (PK) 15 units / mL

H. Lactic Dehydrogenase (LDH) 15 units / mL

i. Met-2 peptide (10 mM) 0.500 mM

j. 50 nM HGFR

2. For a 10 mL reaction buffer add 10 μl of 1 M PEP, 33 μl of 100 mM NADH, 50 μl of 4 M MgC12, 20 μl of 1 M DTT, 6 μL of 500 mM ATP, and 500 μl uL of 10 mM Met-2 peptide in 100 mM HEPES buffer pH 7.5 and vortex / mixture.

3. Add coupling enzymes, LDH and PK, to the reaction mixture. Mix by gentle inversion.

Operating samples

1. Spectrophotometer fixations:

i. Absorbance wavelength (A): 340 nm ii. Incubation time: 10 min.

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220/470 iii. Working Time: 10 min.

iv. Temperature: 37 ° C

2. Add 85 pL of the EC reaction mixture to each well of the assay plate.

3. Add 5 pL of diluted compound to a well on the assay plate.

4. Add 5 pL of 50% DMSO for negative control to the last column of the assay plate.

5. Mix with a multi-channel pipettor or orbital shaker.

6. Pre-incubate for 10 minutes at 37 ° C.

7. Add 10 pL of 500 nM HGFR to each well of the assay plate; the final concentration of HGFR is 50 nM in a total final volume of 100 pL.

8. Evaluate the activity for 10 minutes at A = 340 nm and 37 ° C.

[000429] The following in vitro assays can be employed to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art.

[000430] Several of the assays described herein are performed in an ELISA format (Sandwich Assay linked immunosorbent enzyme) (Voller, and another 1980 linked immunosorbent assay enzyme, Manual of Clinical Immunology, 2nd ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington, DC, pp. 359-371). The general procedure is as follows: a compound is introduced into cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a known ligand activating the receptor is added .

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The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. The non-substrate components of the cell lysate are washed and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared to control cells that have not been contacted with a test compound.

[000431] Currently preferred protocols for conducting ELISA experiments for specific PKs are provided below. However, the adaptation of these protocols to determine the activity of compounds against other RTKs, as well as for CTKs and STKs, is included in the scope of knowledge of those skilled in the art.

[000432] Other assays described here assess the amount of DNA done in response to the activation of a test kinase, which is a general measure of a proliferative response. The general procedure for this assay is as follows: a compound is introduced into the cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a known ligand activates the receptor is added. After incubation at least overnight, a DNA labeling reagent such as 5-bromodeoxyuridine (BrdU) or H3-thymidine is added. The amount of labeled DNA is detected with either an anti - BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound.

MET TRANSFOSPHORILATION ASSAY [000433] This assay is used to assess the levels of phosphotyrosine in a poly (glutamic acid: tyrosine, 4: 1) substrate as a means of identifying agonists / antagonists of met transfosphorylation of the substrate.

Materials and Reagents:

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1. Corning 96-well ELISA plates, Corning Catalog # 25805-96.

2. Poly (glu-tyr), 4: 1, Sigma, Cat. No; P 0275.

3. PBS, Gibco Catalog # 450-1300EB

4. 50 mM HEPES

5. Blocking buffer: Dissolve 25 g of Bovine Serum Albumin, Sigma Cat. In A-7888, in 500 mL of PBS, filter through a 4 qm filter.

6. Purified GST fusion protein containing Met kinase domain, SUGEN, Inc.

7. TBST buffer.

8. 10% aqueous DMSO (MilliQue H2O).

9. 10 mM aqueous Adenosine-5'-triphosphate (dH2O), Sigma Cat. No. A- 5394.

10. 2X Kinase Dilution Buffer: for 100 mL, mix 10 mL of 1M HEPES in pH 7.5 with 0.4 mL of 5% BSA / PBS, 0.2 mL of 0.1 M orthovanadate sodium and 1 mL of 5M sodium chloride in 88.4 mL dH2O.

11. 4X ATP Reaction Mix: for 10 mL, mix 0.4 mL of 1 M manganese chloride and 0.02 mL of 0.1 M ATP in 9.56 mL dH2O.

12. 4X Mixture of Negative Controls: to 10 mL, mix 0.4 mL of 1 M manganese chloride in 9.6 mL of dH2O.

13. NUNC 96-well V-based polypropylene plates, Applied Scientific Catalog # S-72092

14. 500 mM EDTA.

15. Antibody Dilution Buffer: for 100 mL, mix 10 mL of 5% BSA / PBS, 0.5 mL of 5% Carnation® Instant Milk in PBS and 0.1 mL of 0.1 M orthovanadate sodium in 88.4 mL of TBST.

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16. Rabbit polyclonal anti-phosphotyrosine antibody, SUGEN, Inc.

17. Spicy horseradish peroxidase anti-goat rabbit conjugate, Biosource, Inc.

18. ABTS solution: to 1 L, mix 19.21 g of citric acid, 35.49 g of Na2 hPO4 and 500 mg of ABTS with enough dH2O to prepare 1 L.

19. ABTS / H2O2: mix 15 mL of ABST solution with 2 μL of H2O2 five minutes before use.

20. 0.2M HCl

Procedure:

1. Coat ELISA plates with 2 μg of Poly (Glu-Tyr) in 100 μL of PBS, keep overnight at 4 ° C.

2. Blocking plate with 150 μL of 5% BSA / PBS for 60 minutes.

3. Wash the plate twice with PBS, then once with 50 mM Hepes buffer pH 7.4.

4. Add 50 μl of the diluted kinase to all wells. (Purified kinase is diluted with Kinase Dilution Buffer. Final concentration should be 10 ng / well.)

5. Add 25 μL of the test compound (in 4% DMSO) or DMSO alone (4% in dH2O) for controls to the plate.

6. Incubate the kinase / compound mixture for 15 minutes.

7. Add 25 μL of 40 mM MnCl2 to the negative control wells.

8. Add 25 μL of ATP / MnCl2 mixture to all other wells (except negative controls). Incubate for 5 minutes.

9. Add 25 μL of 500 mM EDTA to stop the reaction.

10. Wash the plate 3 times with TBST.

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11. Add 100 qL of rabbit polyclonal anti - Ptyr diluted 1: 10,000 in Antibody Dilution Buffer to each well. incubate, with shaking, at room temperature for one hour.

12. Wash the plate 3 times with TBST.

13. Dilute anti-rabbit antibody conjugated to HRP Biosource 1: 6,000 in Antibody Dilution Buffer. Add 100 qL per well and incubate at room temperature, with shaking, for one hour.

14. Wash the plate 1 time with PBS.

15. Add 100 qL of ABTS / H2O2 solution to each well.

16. If necessary, stop the development reaction with the addition of 100 ql of 0.2 M HCl per well.

17. Read the ELISA reader plate Dynatech MR7000 with the test filter at 410 nM and the reference filter at 630 nM.

INCORPORATION ASSAYS BrdU [000434] The following assays employ cells constructed to express a selected receptor and then evaluate the effect of a compound of interest on ligand-induced DNA synthesis activities by determining the incorporation of BrdU into DNA.

[000435] The following materials, reagents and procedure are general for each of the following BrdU incorporation assays. Variations in specific tests are noted.

General Materials and Reagents:

1. The appropriate ligand.

2. The appropriate built cell.

3. BrdU Labeling Reagent: 10 mM, in PBS, pH 7.4 (Roche Molecular Biochemicals, Indianapolis, IN).

4. FixDenat: fixation solution (Roche MolecularBiochemicals, Indianapolis, IN).

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5. Anti - BrdU-POD: mouse monoclonal antibody conjugated to peroxidase (Chemicon, Temecula, CA).

6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN).

7. PBS Washing Solution: 1X PBS, pH 7.4.

8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA).

General Procedure:

1. The cells are seeded at 8000 cells / well in 10% CS, 2 mM Gln in DMEM, in a 96-well plate. The cells are incubated overnight at 37 ° C in 5% CO2.

2. After 24 hours, the cells are washed with PBS, and then they are fasted from serum in serum-free medium (0% CS DMEM with 0.1% BSA) for 24 hours.

3. On day 3, the appropriate ligand and the test compound are added to the cells simultaneously. Negative control wells receive serum-free DMEM with 0.1% BSA only; positive control cells receive the ligand, but no test compounds. The test compounds are prepared in serum-free DMEM with ligand in a 96-well plate, and serially diluted by 7 test concentrations.

4. After 18 hours of ligand activation, diluted BrdU labeling reagent (1: 100 in DMEM, 0.1% BSA) is added and cells are incubated with BrdU (final concentration is 10 pM) for 1.5 hours.

5. After incubation with labeling reagent, the culture medium is removed by decanting and draining the inverted plate on a paper towel. FixDenat solution is added (50 pl / well) and the plates are incubated at room temperature for 45 minutes on a plate shaker.

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6. The FixDenat solution is removed by decanting and draining the inverted plate onto a paper towel. Milk is added (5% dehydrated milk in PBS, 200 µl / well) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker.

7. The blocking solution is removed by decanting and the wells are washed once with PBS. AntI - BrdU-POD solution is added (1: 200 dilution in PBS, 1% BSA, 50 pl / well) and the plate is incubated for 90 minutes at room temperature on a plate shaker.

8. The antibody conjugate is removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and draining onto a paper towel.

9. TMB substrate solution is added (100 pl / well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection.

10. The absorbance of the samples is measured at 410 nm (in dual wavelength mode with a filter reader at 490 nm, as a reference wavelength) in a Dynatech ELISA plate reader.

HGF-induced BrdU Incorporation Assay

Materials and Reagents:

1. Recombinant human HGF (Cat. No. 249-HG, R & D Systems, Inc. USA).

2. BxPC-3 cells (ATCC CRL-1687).

Remaining Materials and Reagents, as above. Procedure:

1. The cells are seeded at 9000 cells / well RPMI% FBS in a 96 well plate. The cells are incubated

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2. After 24 hours, the cells are washed with PBS, and then they are fasted from serum in 100 μL of serum-free medium (RPMI with 0.1% BSA) for 24 hours.

3. On day 3, 25 qL containing ligand (prepared at 1 qg / mL in RPMI with 0.1% BSA; final HGF concentration is 200 ng / mL) and the test compounds are added to the cells. The negative control wells receive 25 qL of serum-free RPMI with 0.1% BSA only; positive control cells receive the ligand (HGF) but no test compound. The test compounds are prepared at 5 times their final concentration in serum-free RPMI with a 96-well plate, and serially diluted to provide 7 test concentrations. Typically, the highest final concentration of the test compound is 100 qM, and 1: 3 dilutions are employed (i.e., the final test compound concentration range is 0.137 to 100 qM).

4. After 18 hours of ligand activation, 12.5 µL of BrdU labeling reagent (1: 100 in RPMI, 0.1% BSA) is added to each well and the cells are incubated with BrdU (final concentration is 10 qM) for 1 hour.

5. Same as the General Procedure.

6. Same as the General Procedure.

7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution (1: 100 dilution in PBS, 1% BSA) is added (100 qL / well) and the plate is incubated for 90 minutes at room temperature on a plate shaker.

8. Same as the General Procedure.

9. Same as the General Procedure.

10. Same as the General Procedure.

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Animal Models In vivo.

ANIMAL XENOXEST MODELS [000436] The ability of human tumors to develop as xenografts in athymic mice (eg, Balb / c, nu / nu) provides a useful in vivo model for studying the biological response to therapies for human tumors. Since the first successful xenotransplantation of human tumors in athymic mice, (Rygaard and Povisen, 1969, Acta Pathol. Microbial. Scand. 77: 758760), many different human tumor cell lines (eg, breast, lung, genitourinary , gastro-intestinal, head and neck, glioblastoma, bone, and malignant melanomas) have been transplanted and successfully developed in nude mice. The following tests can be used to determine the level of activity, specificity and effect of the different compounds of the present invention. Three general types of assays are useful for evaluating compounds: cellular / catalytic, cellular / biological and in vivo. The purpose of cell / catalytic assays is to determine the effect of a compound on the ability of TK to phosphorylate tyrosines on a known substrate in a cell. The purpose of cell / biological assays is to determine the effect of a compound on the biological response stimulated by a TK in a cell. The purpose of in vivo testing is to determine the effect of a compound on an animal model of a particular disorder such as cancer.

[000437] Cell lines suitable for subcutaneous xenograft experiments include C6 cells (glioma, ATCC # CCL 107), A375 cells (melanoma, ATCC # CRL 1619), A431 cells (squamous cell carcinoma, ATCC # CRL1555), Calu 6 cells ( lung, ATCC # HTB56), PC3 cells (prostate, ATCC # CRL 1435), SKOV3TP5, S114 cells (NIH3T3 fibroblast cell line genetically engineered for NCI cMet and HGF expressions), U

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87MG (human malignant glioma, ATCC HTB 14) and NIH 3T3 fibroblasts genetically engineered to overexpress EGFR, PDGFR, IGF-1R or any other test kinase. The following protocol can be used to perform xenograft experiments:

[000438] Female asthmatic mice (BALB / c, nu / nu) are obtained from Simonsen Laboratories (Gilroy, CA). All animals are kept under clean room conditions in Micro-isolator cages with Alpha-dri beds. They receive sterile rodent feed and water ad libitum.

[000439] Cell lines are grown in an appropriate culture medium (for example, MEM, DMEM, Ham's F10, or Ham's F12 plus 5% to 10% fetal bovine serum (FBS) and 2 mM glutamine (GLN)). All cell culture media, glutamine, and fetal bovine serum are commercially available from Gibco Life Technologies (Grand Island, NY) unless otherwise specified. All cells are developed in a humid atmosphere of 90 to 95% air and 5 to 10% CO2 at 37 ° C. All cell lines are routinely subcultured twice a week and are negative for mycoplasma as determined by the Mycotect (Gibco) method.

[000440] The cells are harvested at or near confluence with 0.05% Trypsin-EDTA and pelleted at 450 x g for 10 minutes. The pellets are resuspended in sterile PBS or culture media (without FBS) to a particular concentration and the cells are implanted in the rear flank of the mice (8 to 10 mice per group, 2-10 x 106 cells / animal). Tumor growth is measured for 3 to 6 weeks using calipers. Tumor volumes are calculated as a length x width x height product unless otherwise indicated. P values are calculated using the Students t test. Test compounds in 50 to 100 pL of excipient (DMSO, or VPD: D5W) can be released

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Met Phosphorylation - Cell Assay

Materials and Reagents:

1. 10 cm Falcon culture dishes.

2. A549 lung carcinoma cells.

3. F12K growth culture medium (with 2% FBS + 2 mM glutamine.

4. F12K assay culture medium (with 0.1% BSA).

5. Fisher cell scrapers.

6. Lysis Buffer (HNTG, 1 mM sodium orthovanidate, mM PMSF and 2 mM sodium fluoride).

7. 1.5 mL of Eppendorf tubes.

8. Eppendorf microcentrifuge.

9. Test reagents BCA A and B (# 23223 and 23224, Pierce).

10. Sample tube spinner.

11. Gel stain container spinner.

5X sample buffer.

13. Novex pre-fused tris-glycine 3% ascrylamide gels.

14. Bio-Rad electrophoresis chamber.

15. SDS-PAGE buffer.

16. TBS (pH 7.6) + 0.1% Triton X-100 (TBST), with and without 5% milk.

17. Western blot transfer buffer.

18. Osmonic nitrocellulose paper.

19. Bio-Rad Transmancha Paper.

20. Gel transfer mechanism.

21. AntI - phosphotyrosine (monoclonal mouse).

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22. Pre-stained patterns by Kaleidoscope Bio-Rad (161-0324).

23. Polyclonal rabbit AntI - h-met (C-28), conjugated and non-conjugated with agarose (# sc-

161 AC and sc-161, Santa Cruz Biotechnology, Inc.).

24. Ig-HRP antI - rabbit and donkey (NA 934, Amersham).

25. Ig-HRP antI - sheep mouse (NA 931, Amersham).

26. SuperSignal West Pico Chemiluminescent Substrate (# 34080, Pierce).

27. Saran wrap.

28. Kodak BioMax exposure cassette.

29. Fuji X-ray film.

30. Kodak film developer.

Procedure:

1. Plaque cells in 10 cm dishes with growth medium with 2% FBS + 2 mM glutamine. Develop until close to the confluence.

2. Fasted serum cells overnight in culture medium with 0.1% BSA.

3. Add drug to the plates, one dose per plate, usually in a 2-fold titration. Add assay medium (with the same concentration of DMSO as the drugs) for any drugs.

4. Incubate plates 4 to 5 hours with the drug, then add HG, 50 ng / mL for 10 minutes.

5. Wash the plates once with PBS, add 400 µl of lysis buffer, and scrape the cells. Collect in 1.5 mL Eppendorf tubes.

6. After about 10 to 20 minutes in the lysis buffer, centrifuge the lysates in a microcentrifuge at full speed (14,000

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g) and collect the supernatants in a separate Eppendorf tube.

7. Determine the protein concentration with the BCA assay reagents.

8. Adjust the sample concentration to 0.5 mg of protein in 0.4 mL, using lysis buffer.

9. Add 15 µl of AC antI - h-met for immunoprecipitation, rotate the samples for 2 hours at 4 ° C.

10. Wash the samples 3 times with lysis buffer and resuspend in 35 µl of 5X sample buffer.

11. Boil the sample at 100 ° C for 10 minutes and microcentrifuge and in a higher setting for 30 minutes to pellet the agarose beads.

12. Load 15 pl each in 2 gels, one for anti-phosphorylation, and the other for anti-h-met. Also load 10 pl of pre-stained patterns, one lens per gel.

13. Place gel around 100 to 125 V, then transfer the gel to nitrocellulose or overnight at 70 mAmps or 1 hour at 500 mAmps.

14. Blocking membranes on the spinner for 1 hour in TBS + 0.1% Triton X-100 (TBST) + 5% PBS. All steps from this point on are at room temperature, unless otherwise stated.

15. Add 0.8 pg / mL antiphosphotyrosine and 0.25 pg / mL antI h-met to the spinner for either 2 hours or overnight.

16. Wash the membranes 3 times 5 minutes each in TBST on the spinner.

17. Add HRP-conjugated antibodies (anti-sheep mouse for anti-phosphotyrosine; anti-donkey rabbit for natI-h-met) at 1: 5000 for approximately 45 minutes on the spinner.

18. Wash the membranes 3 times for 5 minutes each

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19. Add the 2 reagents in the SuperSignal kit together in equal volumes (3 mL + 3 mL for each spot), rotate for 1 to 2 minutes.

20. Wrap the stains in Saran Wrap and tie tightly inside the exposure cassette.

21. In the dark room with only the safety light on, place a sheet of film inside the cassette. After a while, remove the film and place in the developing machine for automatic processing. Experiment with the exposure time to obtain appropriate exposure.

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TABLES

Table 1 No. Structure Name Met ICso (μΜ) ¹ H-NMR MS m / z (M + 1) there) Br 5-Bromo-3- (2,6dichlorobenciloxy) -pyridin2-ylamine 5.3 (400 MHz, DMSO-d ₆ ) δ 7.62 (m, 1H), 7.56 (m, 2H), 7.46 (m, 2H), 5.80 (s, 2H), 5.22 ( s, 2H) 349 l (b) ° .ç. nh ₂ 3-Benciloxy-5bromo-pyridin-2ylamine > 20 (400 MHz, DMSO- d ₆ ) δ 7.56 (d, J = 2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 (m, 2H), 7 , 32 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 2 Hz, 1H), 5.95 (s, 2H), 5.14 (s, 2H) 280 l (c) 1 AVA · nh ₂ 5-Bromo-3- (2,6difluoro-bencilóxi) - pyridin-2-ylamine 40% a 20 μΜ (400 MHz, DMSO-d ₆ ) δ 7.60 (d, 1H), 7.52 (m, 1H), 7.40 (d, 1H), 7.18 (m, 2H), 5.81 ( br, s, 2H), 5.12 (s, 2H) 315 (M +) l (d) jD X ^Br 1 li NHj 5-Bromo-3- (2bromobenciloxy) -pyridin2-ylamine > 20 (400 MHz, DMSO-d ₆ ) δ 7.65 (m, 2H), 7.60 (d, 1H), 7.42 (m, 2H), 7.30 (d, 1H), 5.94 ( s, 2H), 5.13 (s, 2H) 357 (M +) l (e) 5-Bromo-3- (2-chloro-6-fluorbenciloxy) -pyridin2-ylamine > 20 (400 MHz, DMSO-d ₆ ) δ 7.80- 7.30 (m, 5H), 5.80 (brs, 2H), 5.15 (s, 2H) 331 l (f) xx ^ · 5-Bromo-3- (2-chloro-4-fluorbenciloxy) -pyridin2-ylamine (400 MHz, DMSO-d ₆ ) δ 7.80 - 7.20 (m, 5H), 5.95 (brs, 2H), 5.10 (s, 2H) 331

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Table 1 No. Structure Name Met IC50 (μΜ) ¹ H-NMR In m / z (M + 1) IG) O O 5-Bromo-3- (2,4dichloro-benciloxypyridin-2-ylamine (400 MHz, DMSO-d ₆ ) δ 7.80- 7.50 (m, 5H), 6.20 (brs, 2H), 5.20 (s, 2H) 348 l (h) or-4 2- (2-amino-5bromo-pyridin-3yloxymethyl) benzonitrile (400 MHz, DMSO-d ₆ ) δ 7.90- 7.30 (m, 6H), 5.90 (brs, 2H), 5.20 (s, 2H) 304 (M +) l (i) ,,, ή M-CF, * · * 5-Bromo-3- (2trifluoromethyl benciloxy) -pyridin2-ylamine (400 MHz, DMSO-d ₆ ) δ 7.80- 7.30 (m, 6H), 6.00 (brs, 2H), 5.25 (s, 2H) 347 IO) Br 5-Bromo-3- (4terf-butylbenciloxy) -pyridin2-ylamine (400 MHz, DMSO-d ₆ ) δ 7.50- 7.20 (m, 6H), 5.85 (brs, 2H), 5.05 (s, 2H), 1.25 (s, 9H) 335 (M +) l (H) dr ° 4 5-Bromo-3- (2-chloro-benciloxy) pyridin-2-ylamine (400 MHz, DMSO-d ₆ ) δ 7.70 - 7.20 (m, 6H), 5.90 (brs, 2H), 5.15 (s, 2H) 313 l (l) 5-Bromo-3- (2-chloro-3,6-difluorborboxy) -pyridin2-ylamine (CDCb, 300 MHz) δ 4.7- 4.8 (brs, 2H), 5.21 (s, 2H), 7.03 - 7.10 (dt, 1H, J 4,1,9,1), 7,17- 7,25 (m, 2H), 7,75- 7,76 (d, J, 1.86), l (m) 7 'A' vV.V nh ₂ 5-Bromo-3- (3-fluoro-2-trifluoromethyl-benciloxy) pyridin-2-ylamine 365

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Table 1 No. Structure Name Met IC50 (μΜ) ¹ H-NMR In m / z (M + 1) l (n) O^-2- z O 5-Bromo-3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-2-ylamine (CDCb, 300 MHz) 0.18 - 1.95 (d, 3H), 4.7- 5.0 (brs, 2H), 5.9- 6.01 (q, 1H), 6.8-6.95 (d, 1H), 7.01- 7.2 (t, 1H), 7.4- 7.45 (m, 1H), 7.8- 7.85 (d, 1H), l (o) 5-Bromo-3- [1- (2chloro-3,6-difluorophenyl) -ethoxy] pyridin-2-ylamine 364 II (a) Br Cl N ^ | 5-Bromo-3- (2,6dichlorobenciloxy) pyrazin-2-ylamine (400 MHz, DMSO- d ₆ δ 5.45 (s, 2H), 6.45 (s, 2H), 7.50 (m, 3H), 7.63 (s, 1H) 350 ll (b) Br? iM Y] ⁰ i NH, 5-Bromo-3- (2-chloro-3,6-difluoro-stencil) pyrazin-2-ylamine (300 MHz, CDCb) δ 7.7 (s, 1H), 7.23- 7.16 (m, 1H), 7.09-7.01 (m, 1H), 5.53 (s, 2H), 4.72 (s, 2H) 351 ll (c) A 1 A nh ₂ 5-Bromo-3- [1- (2chloro-3,6-difluorophenyl) -ethoxy] pyrazin-2-ylamine (400 MHz, DMSO-d ₆ ) δ 1.75 (d, 3H), 6.26 (m, 1H), 6.46 (s, 2H), 7.28 (m, 1H), 7.41 ( m, 1H), 7.52 (s, 1H) 365 At the Structure Nombre Met IC50 (μΜ) ¹ H- NMR MS m / z (M + 1) II (d) 1YJÒ LA ₀ nh, 5-Bromo-3- [1- (2chloro-3,6-difluorophenyl) -2-methylpropoxy] -pyrazin2-ylamine (400 MHz, DMSO-d ₆ ) δ 0.92 (d, 3H), 1.17 (m, 3H), 2.57 (m, 1H), 5.75 (d, 1H), 6.49 ( s, 2H), 7.24 (m, 1H), 7.40 (m, 1H), 7.54 (s, 1 H) 393

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Table 1 No. Structure Name Met IC50 (μΜ) ¹ H-NMR In m / z (M + 1) ll (e) çi | ίΥθν Μό. nh, 5-Bromo-3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyrazin-2-ylamine (400 MHz, DMSO-d ₆ ) δ 1.74 (d, 3H), 6.40 (m, 1H), 6.52 (brs, 2H), 7.30 (m, 1H), 7.48 ( m, 1H), 7.56 (s, 1H); MS m / z382 (M + 1), 382 ll (f) Br V ^F 3 ⁰ NH, 5-Bromo-3- (3fluor-2trifluoromethylbenciloxy) pyrazin-2-ylamine 366

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1-1 4- [6-amino-5- (2,6dichloro-benciloxy) -pyridin-3-yl] phenol 0.279 See example (400 MHz, DMSO- de) δ 9.36 (s, 1H, OH), 7.77 (s, 1H), 7.54 (d, J = 5.2 Hz, 2H), 7.43 (m 4H) 6.78 (d, J = 5.2 Hz, 2H), 5.49 (br, s, 2H, NH ₂ ), 5.30 (s, 2H, CH2), 362 I-2 3- (2,6-Dichlorobenciloxy) -5 [4- (2morpholin-4-yletoxy) -phenyl] pyridin-2-ylamine 0.58 See example (400 MHz, DMSO- de) δ 7.81 (d, J = 1.2 Hz, 1H), 7.53 (m, 3H), 7.48 (m, 3H), 6.97 (d, 2H ), 5.53 (br, s, 2H, NH ₂ ), 4.08 (t, 2H), 3.55 (t, 4H), 2.68 (t, 2H), 2.46 (t, 4H ), 374 I-3 çr ° ^ O 3- (2,6-Dichlorobenciloxy) -5- [3- (2morfolin-4-yletoxy) -phenyl] pyridin-2-ylamine 0.59 See example (400 MHz, DMSO- de) δ 7.89 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 5.2 Hz, 2H), 7.51 (d, J = 1 , 2 Hz, 1H), 7.44 (dd, 1H), 7.28 (dd, 1H), 7.18 (m, 2H), 6.83 (dd, 1H), 5.65 (br, s, 2H), 5.33 (s, 2H), 4.12 (t, 2H), 3.55 (t, 6H), 2.68 (t, 2H), 2.46 (t, 2H) 475 I-4 M-c NH, 3- (2,6-Dichlorobenciloxy) -5- (1 Hindol-4-yl) -pyridin2-ylamine 1.4 See example (400 MHz, DMSO- de) δ 11.18 (s, 1H, NH), 7.87 (d, 1H), 7.5 (d, 2H), 7.46 (d, 2H), 7.36 (m, 1H), 7.33 (m, 1H), 7.12 (t, 1H), 7.03 (d, 1H), 6.49 (d, 1H), 5.61 (br, s, 2H, NH2), 5.31 (s, 2H, CH2), 384 I-5 03 UL _to 1 «, 3- [2-chloro-6- (1 Hindol-4-yl) benciloxy] -5- (1 Hindol-4-yl) -pyridin2-ylamine 4.71 See example 465

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1-6 ά + κ 2- [6-amino5- (2,6-dichlorobenciloxy) -pyridin3-yl] -pyrrole-1 carboxylic acid terbutil > 20 See example 435 1-7 Çh 3- (2,6-dichlorobenciloxy) -5- (1 Hpirrol-2-yl) -pyridin2-ylamine 4.25 See example (400 MHz, DMSO- de) δ 11.05 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.50 (m, 2H), 6.75 (s, 1H), 6.35 (s, 1H), 6.05 (s, 1H), 5.50 (br, s, 2H), 5.30 (s, 2H), 335 1-8 ô LA _to NU 3- (2,6-dichlorobenciloxy) -5- (4-fluoro-phenyl) -pyridin2-ylamine 8.01 See example (400 MHz, DMSO, de) δ 7.89 (s, 1H), 7.69 (m, 2H), 7.58 (m, 3H), 7.48 (m, 1H), 7.23 (m, 2H), 5.70 (br, s, 2H), 5.35 (s, 2H), 364 1-9 α ΗΗ> 3- (2,6-dichlorobenciloxy) -5-phenylpyridin-2-ylamine 3.9 See example (400 MHz, DMSO- de) δ 7.89 (d, J = 2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.57 (d, J = 2 Hz, 1H), 7.54 (m, 2H), 7.43 (m, 1H), 7.40 (m, 2H), 7.26 ( m, 1H), 5.68 (br, s, 2H), 5.34 (s, 2H), 345 Ι- ΙΟ 3- (2,6-Dichlorobenciloxy) -5- (2-fluoro-phenyl) -pyridin2-ylamine 6.09 See example (400 MHz, DMSO- de) δ 7.76 (d, 1H), 7.55 (m, 2H), 7.54 (m 1H), 7.46 (m, 2H), 7.32 (m, 1H), 7.25 (m, 2H), 5.78 (br, s, 2H), 5.28 (s, 2H), 364 1- 11 The Ã-Ό-γ ΝΗ, 3- (2,6-Dichlorobenciloxy) -5- (3-fluoro-phenyl) -pyridin2-ylamine 13.8 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.58- 7.44 (m, 7H), 7.17 (m 1H), 5.78 (br, s, 2H), 5.35 (s, 2H), 364

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 12 NH, Χρ, χρ, NH, 5- (4-amino-phenyl) - 3- (2,6-dichlorobenciloxy) -pyridin2 ylamine 0.606 See example (400 MHz, DMSO- de) δ 7.75 (d, 1H), 7.54 (dd, 4H), 7.47 (m, 1H), 7.40 (d, 1H), 7.29 (dd , 2H), 6.60 (dd, 2H), 5.44 (br, s, 2H), 5.31 (s, 2H), 5.15 (br s, 2H), 360 I- 13 J, CH> NH, N- {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin- 3-yl] -phenyl} methanesulfonamide 0.44 See example (400 MHz, DMSO- de) δ 9.70 (s, 1H), 7.86 (d, 1H), 7.59 (m, 1H), 7.56 (m, 2H), 7.55 (m, 1H), 7.45 (m, 2H), 7.22 (dd, 2H), 5.63 (br, s, 2H), 5.33 (s, 2H), 2.95 (s, 3H), 439 I- 14 O Bad N- {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -phenyl} acetamide > 20 See example (400 MHz, DMSO- de) δ 9.94 (s, 1H), 7.86 (d, 1H), 7.59 (m, 1H), 7.57 (m, 2H), 7.54 (m, 2H), 7.48 (m, 2H), 5.61 (br, s, 2H), 5.33 (s, 2H), 2.04 (s, 3H), 402 I- 15 çr χ-μ? 3- [6-amino-5- (2,6dichloro-benciloxy) -pyridin-3-yl] phenol 1.34 See example 400 MHz, DMSO- de) δ 7.83 (s, 1H), 7.55 (dd, 2H), 7.46 (m 2H), 7.19 (m, 1H), 7.10 (m, 1H ), 7.04 (m, 1H), 6.98 (m, 1H), 6.69 (m, 1H), 5.67 (br, s, 2H), 5.33 (s, 2H), 360 I- 16 3- (2,6-Dichlorobenciloxy) -5- (4-methoxy-phenyl) pyridin-2-ylamine 6.55 See example (400 MHz, DMSO- de) δ 7.83 (s, 1H), 7.62- 7.54 (m, 4H), 6.97 (dd, 2H), 6.66 (dd, 2H), 5.58 (br, s, 2H), 5.33 (s, 2H), 3.77 (s, 3H), 357 I- 17 (ΓΎ 5- (3-amino-phenyl) - 3- (2,6-dichlorobenciloxy) -pyridin2-ylamine 1.07 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.68 (m, 1H), 7.45 (m, 1H), 7.36 (t, 1H), 7.28 (d, 1H), 7.22 (m, 1H), 6.93 (d, 1H), 6.86 (d, 1H), 6.64 (dd, 1H), 5.34 (s, 2H), 4.73 (brs, 2H), 4.12 (brs, 2H), 360

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 18 3- (2,6-dichlorobenciloxy) -5- (3trifluoromethoxyphenyl) - pyridin-2ylamine > 20 See example (300 MHz, CDCb) δ 7.95 (d, 1H), 7,497.24 (m, 7H), 7.17 (m, 1H), 5.39 (s, 2H), 4.81 (brs, 2H), 429 I- 19 XH, 2- [6-amino-5- (2,6dichloro-bazenzyloxy) -pyridin-3-yl] phenol 2.16 See example (300 MHz, CDCb) δ 7.81 (d, 1H), 7.66 (m, 2H), 7.52 (m, 1H), 7.37 (d, 1H), 726 (m, 3H), 6.99 (m, 2H), 5.32 (s, 2H), 4.77 (brs, 2H) 361 I- 20 Çl. _the jQ Ή 3- (2,6-dichlorobenciloxy) -5- (2-phenoxy-phenyl) pyridin-2-ylamine > 20 See example (300 MHz, CDCb) δ 7.88 (d, 1H), 7.66 (m, 2H), 7.45 (m, 3H), 7.34 (m, 2H), 7.26 (m, 3H ), 7.07 (m, 2H), 6.93 (, 2H), 5.16 (s, 2H), 4.66 (brs, 2H), 437 I- 21 what U <Ιλ 3- (2,6-dichlorobenciloxy) -5- (3,4difluoro-phenyl) pyridin-2-ylamine 14.3 See example (300 MHz, CDCb) δ 7.89 (d, 1H), 7.40 (d, 2H), 7.26 (m, 5H), 5.37 (s, 2H), 4.80 (brs, 2H ), 381 I- 22 THE ά? \ 3- (2,6-dichlorobenciloxy) -5- (3isopropyl-phenyl) pyridin-2-ylamine 15.9 See example (300 MHz, CDCb) δ 7.96 (d, 1H), 7.40- 7.15 (m, 8H), 5.38 (s, 2H), 4.73 (brs, 2H), 2.98 (m, 1H), 1.31 (d, 6H), 387 I- 23 η. If 3- (2,6-dichlorobenciloxy) -5- (2trifluoromethylphenyl) -pyridin-2ylamine > 20 See example (300 MHz, CDCb) δ 7.76 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.27 (m, 2H), 7.17 (s, 1H), 5.29 (s, 2H), 4.78 (brs, 2H), 413 I- 24 Ατ ^ ο'Ύ LAc «H. 3- (2,6-dichlorobenciloxy) -5- (2-methoxy-phenyl) pyridin-2-ylamine 11.5 See example (300 MHz, CDCb) δ 7.89 (s, 1H), 7.41- 7.24 (m, 6H), 7.02 (m, 2H), 5.32 (s, 2H), 4.69 (brs, 2H), 3.84 (s, 3H), 375

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 25 f jml 3- (2,6-dichlorobenciloxy) -5- (4trifluoromethylphenyl) -pyridin-2ylamino > 20 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz, 1H), 7.66 (m, 3H), 7.36 (m, 3H), 7.29 (m, 2H), 7.89 (s, 1H), 5.38 (s, 2H), 4.93 (brs, 2H), 413 1- 26 Pi « Sn ιΛ ° ά-Φ nh, N- {2- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -phenyl} methanesulfonamide > 20 See example (300 MHz, CDCb) δ 8.75 (brs, 1H), 7.70- 7.14 (m, 9H), 5.31 (s, 2H), 5.16 (brs, 2H), 3.16 (s, 3H) 438 1- 27 XH 0 ”^ T ^ ^S ° ^X | ^{: 5N} * kA _a {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -phenyl} -methanol 2.5 See example (300 MHz, CDCb) δ 7.84 (d, J = 1.8 Hz, 1H), 7.66 (m, 2H), 7.63-7.18 (m, 6H), 5.36 (s, 2H), 4.75 (d, 2H), 4.73 (brs, 2H), 2.5 (br, 1H), 375 1- 28 5benzo) [1,3] dioxol5-yl-3- (2,6-dichlorobenciloxy) -pyridin2-ylamine 8.5 See example (300 MHz, CDCb) δ 7.88 (d, J = 1.5 Hz, 1H), 7.37 (m, 2H), 7.29 (m, 2H), 6.99 (d, 2H), 6.87 (d, 1H), 5.99 (s, 2H), 5.36 (s, 2H), 4.74 (brs, 2H), 389 1- 29 Ç ^ cAt Οζ * <> 3- (2,6-dichlorobenciloxy) -5- (2trifluoromethoxyphenyl) -pyridin-2ylamine > 20 See example (300 MHz, CDCb) δ 7.82 (s, 1H), 7.477.25 (m, 8H), 5.33 (s, 2H), 4.82 (brs, 2H), 429 1- 30 Jj. LA _to H. 3- (2,6-dichlorobenciloxy) -5- (4methyl-thiophen-2-yl) pyridin-2-ylamine 3.5 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.9 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 2H), 7.29 (m, 2H), 7.00 (d, J = 1.1 Hz, 1H), 6.80 (s, 1H), 5.34 (s, 2H), 4.80 (brs, 2H), 2.28 (s, 3H), 365 1- 31 _p CCn 5- (2-benciloxyphenyl) -3- (2,6dichloro-benciloxy) pyridin-2-ylamine > 20 See example (300 MHz, CDCb) δ 7.90 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.31 (m, 10H), 7, 06 (m, 2H), 5.06 (s, 2H), 4.77 (br s, 2H), 451

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 32 QT ⁰ 3- (2,6-dichlorobenciloxy) -5- (3-methoxy-phenyl) pyridin-2-ylamine 4.01 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.39-7.11 (m, 4H), 7.13 (d, J = 7.7 Hz, 2H), 7.07 (t, J = 2.1 Hz, 1H), 6.88 (dd, J = 8.2 Hz, 2.1 Hz, 1H), 5.36 (s, 2H), 4.78 (brs, 2H), 3.87 (s, 3H), 375 1- 33 3- (2,6-dichlorobenciloxy) -5- (1 Hindol-2-yl) -pyridin2-ylamine 7.5 See example (300 MHz, CDCb) δ 8.47 (brs, 1H), 8.04 (s, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.62-7.11 (m, 6H), 6.71 (d, J = 1.3 Hz, 1H), 6.66 (dd, J = 7.7 Hz, 2.1 Hz, 1H), 5.29 (s, 2H), 4.73 (brs, 2H), 384 1- 34 J 5- (4-benciloxy-3fluor-phenyl) -3- (2,6dichloro-benciloxy) - pyridin-2-ylamine 13.5 See example (400 MHz, DMSO- de) δ 5.20 (s, 2H), 5.32 (s, 2H), 5.65 (s, 2H), 7.25 (t, 1H), 7.33 (m, 1H), 7.39 (m, 3H), 7.46 (m, 3H), 7.51 (m, 4H), 7.88 (s, 1H), 469 1- 35 Ο ^, ΟΜ 0 4- [6-amino5- (2,6-dichlorobenciloxy) -pyridin- acid 3-ilJfeniljbenzoico 12.8 See example (400 MHz, DMSO- de) δ 7.98 (s, 1H), 7.92 (d, J = 5.6 Hz, 2H), 7.75 (d, J = 4.8 Hz, 2H), 7.55 (d, J = 5.2 Hz, 1H), 7.54 (dd, 2H) , 7.45 (m, 1H), 5.8 (br, S, 2H), 5.34 (s, 2H), 390 1- 36 Q ^ NH 4- [6-amino-5- (2,6dichloro-benciloxy) pyridin-3-yl] -N- (2diethylamine-ethyl) benzamide 0.99 See example (400 MHz, DMSO- de) δ 8.45 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 5.6 Hz, 2H), 7.60 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 5.2 Hz, 2H), 7.44 (dd, 1H), 5.77 (br, s, 2H), 5.34 (s, 2H), 3.3 (m, 4H), 2.6 (m, 4H), 0.99 (t, 6H), 487

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 37 / <5c? 4- [6-amino-5- (2,6dichloro-benciloxy) pyridin-3-yl] -N- (3dethylaminepropyl) -benzamide 0.82 See example (400 MHz, DMSO- de) δ 8.60 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.75 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.60 (m, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 5.70 (br, s, 2H), (s, 2H ), 3.3 (m, 4H), 2.6 (m, 4H), 1.7 (m, 2H), 1.0 (t, 6H), 501 1- 38 όζ-Λ {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl) -methanone 1.02 See example (400 MHz, DMSO- de) δ 7.95 (d, J = 2Hz, 1H), 7.72 (dd, J = 6, 1.6 Hz, 2H), 7.59 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J = 6, 1.2 Hz, 1H), 7.40 (dd, J = 6, 1.6 Hz, 2H), 5.76 (br, s, 2H), 5.35 (s, 2H), 3.6 (m, 4H), 2.3 (m, 4H), 2.2 (s, 3H), 471 1- 39 o ^e ”Cçí {4- (6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -pheni1} - [(2H) 2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl] -methanone 0.062 / 0.11 / 0.2 (Hi 0.04) See example (400 MHz, DMSO- de) δ 7.96 (d, 1H), 7.72 (dd, 2H), 7.59 (m, 2H), 7.54 (m, 2H), 7.47 (m, 2H), 5.76 (br, s, 2H), 5.36 (s, 2H), 4.35 (m, 1H), 3.5 (d, 2H), 3.0 (m, 4H), 1.7-2.0 (m, 10H), 525 1- 40 Ço έζ * <= {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -phenyl} - [(2S) 2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl] -methanone 0.21 See example (400 MHz, DMSO- de) δ 7.93 (d, 1H), 7.68 (dd, 2H), 7.57 (d, 1H), 7.54 (dd, 2H), 7.47 (m, 2H), 7.44 (m, 1H), 5.74 (br, s, 2H), 5.34 (s, 2H), 3.45 (m, 1H), 3.3 (m, 4H), 2.46 (m, 2H), 1.95 (m, 2H), 1.84 (m, 4H), 1.63 (m, 4H), 526

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 41 «JCr ⁰ {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin- 3-11] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.35 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.70 (dd, 2H), 7.55 (d, 1H), 7.48 (dd, 2H), 7.41 (m, 1H), 7.39 (m, 2H), 5.76 (br, s, 2H), 5.35 (s, 2H), 3.0 (m, 4H), 2.6 (m, 4H), 2.25 (s, 1H), 1.89 (m, 4H), 1.66 (m, 4H), 525 I- 42 0 {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -phenyl} - [4- (2hydroxy-ethyl) piperidin-1 -II] methanone 0.56 See example (400 MHz, DMSO- de) δ 7.94 (d, 1H), 7.71 (dd, 2H), 7.70 (d, 1H), 7.59 (dd, 2H), 7.55 (m, 1H), 7.45 (m, 2H), 5.76 (br, s, 2H), 5.35 (s, 2H), 4.35 (t, 2H), 3.60 (m, 1H), 3.44 (m, 2H), 3.0 (m, 2H), 1.68 (m, 2H), 1.40 (m, 2H), 1.37 (m, 2H), 500 I- 43 0 Μ- _α · η {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin- 3-11] -phenyl} - [(3S) - 3-dimethylaminopyrrolidin-1 - II] methanone 0.47 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.75 (dd, 2H), 7.57 (d, 1H), 7.55 (dd, 2H), 7.48 (m, 1H), 7.46 (m, 2H), 5.76 (br, s, 2H), 5.35 (s, 2H), 3.60 (m, 1H), 3.0 (m, 2H), 2.2 (s, 3H), 2.1 (s, 3H), 1.15 (m, 2H), 485 I- 44 ₀ 0? JII Γί ° _Λ (Ή {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -phenyl} - [(3R) 3-dimethylamino pyrrolidin-1 -II] methanone 0.65 See example (400 MHz, DMSO- de) δ 7.95 (m, 1H), 7.72 (m, 2H), 7.60 (m, 1H), 7.55 (m, 2H), 7.46 (m, 3H), 5.76 (br, s, 2H), 5.35 (s, 2H), 3.50 (m, 3H), 3.0 (m, 2H), 2.1 (s, 3H), 2.05 (s, 3H), 1.1 (m, 2H), 485

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 45 {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -phenyl} - [(3S) - 3cyclopropylaminomethyl-piperidin-1 yl] -methanone 0.77 See example (400 MHz, DMSO- de) δ 7.94 (d, 1H), 7.77 (m, 2H), 7.57 (m, 2H), 7.55 (m, 1H), 7.46 (dd, 1H), 7.39 (m, 2H), 5.79 (s, 2H), 5.35 (s, 2H), 4.4 (m, 1H), 3.6 (m, 1H), 2.6-3.0 (m, 4H), 1.4- 1.8 (m, 8H), 0.8 (m, 2H), 526 1- 46 {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -N- (2-hydroxy- 3-pyrrolidin-1 -IIpropyl) benzamide 0.2 See example (400 MHz, DMSO- de) δ 8.48 (m, 1H), 7.99 (d, 2H), 7.88 (m, 2H), 7.75 (m, 2H), 7.61 (d , 1H), 7.57 (m, 2H), 7.46 (dd, 1H), 5.79 (s, 2H), 5.36 (s, 2H), 4.8 (m, 1H), 3.75 (m, 1H), 3.44 (m, 1H), 3.18 (m, 1H), 2.53 (m, 4H), 2.40 (m, 1H), 1.67 (m, 4H) 515 1- 47 {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] phenyl} - [(2S) -2 (3-fluoro-piperidin1-ylmethyl) pyrrolidin-1 -II] methanone 0.42 See example 557 1- 48 0 ιίιΓ ^{ζχ ο>} τ ^> {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin- 3-11] phenyl} - (4cyclopropylpiperazin-1 -II) methanone 1.67 See example 497 1- 49 d α jr-N {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] phenyl} - {(2H) -2 [cyclopropylmethylamino) - methyl] pyrrolidin-1 -II} methanone 0.37 See example (400 MHz, DMSO- de) δ 7.92 (d, 1H), 7.67 (m, 2H) 7.54 (m, 2H), 7.49 (m, 2H), 7.43 (m, 2H), 5.73 (s, 2H), 5.32 (s, 2H), 4.2 (m, 1H), 3.5 (m, 1H), 3.28 (m, 4H), 2.0-1.7 (m, 6H), 1.18 (m, 4H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 50 Λ the y-tT {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -N- cyclopropylmethyl-N- (2H) pinolidin-2-ylmethylbenzamide 0.29 See example (400 MHz, DMSO- de) δ 8.16 (d, 1H), 7.61 (d, 1H), 7.38 (m, 2H), 7.23-7.18 (m, 4H), 7.09 (m, 1H), 5.44 (s, 2H), 4.98 (s, 2H ), 4.05 (m, 1H), 3.2 (m, 1H), 3.1 (m, 1H), 2.93 (m, 8H), 2.78 (m, 2H), 2.10 (m, 4H) , 525 1- 51 q / {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] -N- (2-hydroxy- 3-pyrrolidin-1 -IIpropyl) -N-methylbenzamide 0.71 See example (400 MHz, DMSO- de) δ 7.90 (m, 1H), 7.76 (m, 1H), 7.63 (m, 2H), 7.52 (d, 2H), 7.50 (m, 2H), 7.40 (m, 1H), 5.69 (s, 2H), 5.30 (s, 2H), 3.70 (m, 1H), 2.96 (s, 3H), 2.44 (m, 4H), 2.34 (m, 4H), 1.75 (m, 4H), 529 I- 52 OH £> y-b o \ 7 α H/ {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11] phenyl} - {(2S) -2 [(3R) -3-hydroxypyrrolidin-1 ylmethyl] -pyrrolidin- 1-il} -methanona 0.53 See example (400 MHz, DMSO- de) δ 7.96 (d, 1H), 7.70 (m, 2H), 7.60 (m, 1H), 7.57 (m, 1H), 7.55 (m, 3H), 7.46 (m, 1H), 5.78 (s, 2H), 5.37 (s, 2H), 4.3 (m, 1H), 3.6 (m, 4H), 3.2 (m, 4H), 1.9 (m, 4H) , 1.24 (m, 4H), 541 I- 53 ιΓ * ⁵ *] * ⁰ * ⁴ _o - $ NHg 3- [6-amino5- (2,6-dichlorobenciloxy) -pyridin3-yl] -benzoic acid 16 See example (400 MHz, DMSO- de) δ 8.13 (m, 1H), 7.91 (d, 1H), 7.98 (m, 2H), 7.56 (dd, 2H), 7.54 (m , 2H), 7.47 (m, 1H), 5.76 (s, 2H), 5.36 (s, 2H), 389 I- 54 άζ? ^hh > {3- [6-amino-5 (2,6-dichloro-benciloxy) -pyridin-3-yl] phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-l-yl] methanone 2.5 See example (400 MHz, DMSO- de) δ 7.93 (d, 1H), 7.74 (m, 2H), 7.56 (m, 3H), 7.46 (m, 2H), 7.36 (m, 1H), 5.74 (s, 2H), 5.35 (s, 2H), 4.40 (m, 1H), 3.40 (d, 2H), 3.0 (m, 4H), 1.7-2.0 (m, 10H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 55 9 '^λ>Κ' ^0Η Ace of T {4- [6-amino5- (2,6-dichlorobenciloxy) -pyridin3-yl] -phenoxy} acetic acid 2.41 See example (400 MHz, DMSO- de) δ 7.81 (d, 1H), 7.56 (m, 2H), 7.48 (m, 4H), 6.87 (m, 2H), 5.53 (s, 2H), 5.32 (s, 2H), 4.33 (s, 2H) 419 1- 56 'The 2- {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-yl] -phenoxy} -1 [(2H) -2-pyrrolidin1-ylmeltypyrrolidin-1 -II] ethanone 0.53 See example (400 MHz, DMSO- de) δ 7.77 (d, 1H), 7.52 (d, 1H), 7.47 (m, 3H), 7.41 (m, 2H), 6.88 (m , 2H), 5.51 (s, 2H), 5.28 (s, 2H), 4.67 (s, 2H), 4.20 (m, 1H), 3.42 (m, 2H), 1.82 (m, 4H), 1.96 (m, 10H), 555 1- 57 P a W 2- {4- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3yl] -phenoxy} -1 [(2S) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -ethanone 0.5 See example (400 MHz, DMSO- de) δ 7.82 (d, 1H), 7.57 (d, 1H), 7.52 (m, 3H), 7.45 (m, 2H), 6.93 (m, 2H), 5.56 (s, 2H), 5.33 (s, 2H), 4.72 (s, 2H), 4.20 (m, 1H), 3.5 (m, 2H), 2.52 (m, 6H), 1.85 (m, 4H), 1.66 (m, 4H) 555 1- 58 HN-i Çj f O Af-cAp <A _to NH, 3- (2,6-dichlorobenciloxy) -5- (1 Hindol-5-yl) -pyridin2-ylamine 4.3 See example (400 MHz, DMSO- de) δ 11.05 (s, 1H, NH), 7.87 (d, 1H), 7.76 (m, 1H), 7.57 (m, 3H), 7.40 - 7.48 (m, 2H), 7.34 (m, 2H), 6.44 (m, 1H), 5.49 (br, s, 2H, NH2), 6.36 (s, 2H, CH ₂ ) 384 1- 59 &O- ape 3- (2,6-dichlorobenciloxy) -5- [3- (1 methyl-1,2,3,6tetrahydro-pyridin4-11) -1 H-indol-5-yl] pyridin-2-ylamine 1.57 See example (400 MHz, DMSO- de) δ 11.35 (d, 1H, NH), 7.95 (s, 1H), 7.89 (d, 1H), 7.55 (m, 4H), 7.45 (m, 2H), 7.39 (dd, 1H), 6.25 (m, 1H), 5.54 (br, s, 2H, NH2), 5.37 (s, 2H, CH2), 3.77 (m, 2H), 3.32 (m, 2H), 2.82 (m, 2H), 2.80 (s, 3H), 480

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 60 3- (2,6-dichlorobenciloxy) -5- [3- (1 methyl-piperidin-411) -1 H-indol-5-yl] pyridin-2-ylamine 3.04 See example (400 MHz, DMSO- de) δ 10.9 (d, 1H, NH), 7.90 (d, 1H), 7.80 (s, 1H), 7.55 (m, 4H), 7.46 (m , 2H), 7.32 (dd, 1H), 5.50 (br, s, 2H, NH ₂ ), 5.38 (s, 2H, CH ₂ ), 3.32 (m, 2H), 3, 02 (m, 2H), 2.90 (m, 1H), 2.67 (s, 3H), 2.10 (m, 2H), 1.98 (m, 2H), 481 1- 61 NH. 3- (2,6-dichlorobenciloxy) -5- (3morfolin-4-ylmethyl- 1 H-indol-5-yl) - pyridin-2-ylamine 1.19 See example (400 MHz, DMSO- de) δ 2.31 (m, 4H), 3.55 (m, 4H), 3.66 (s, 2H), 5.26 (s, 2H), 5.45 (s , 2H), 7.22 (s, 1H), 7.34 (m, 2H), 7.48 (m, 2H), 7.57 (m, 2H), 7.80 (s, 1H), 7.85 (s, 1H), 10.92 (brs, 1H) 483 I- 62 Or f Xj, nh, 3- (2,6-dichlorobenciloxy) -5- (3piperidin-1-ylmethyl- 1 H-indol-5-yl) - pyridin-2-ylamine 1.41 See example (300 MHz, CDCb) δ 1.43 (m, 2H), 1.60 (m, 4H), 2.50 (m, 4H), 3.76 (s, 2H), 4.65 (brs, 2H ), 5.40 (s, 2H), 7.19 (s, 1H), 7.27 (m, 1H), 7.38 (m, 5H), 7.87 (s, 1H), 8.01 (d, J = 1.7 Hz, 1H), 8.17 (brs, 1H) 481 I- 63 not like _a k 3- (2,6-dichlorobenciloxy) -5- (3pyrrolidin-1-ylmethyl- 1 H-indol-5-yl) - pyridin-2-ylamine 1.34 See example (300 MHz, CDCb) δ 1.79 (m, 4H), 2.62 (m, 4H), 3.88 (s, 2H), 4.64 (brs, 2H), 5.40 (s, 2H ), 7.21 (d, J = 2.3 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), 7.84 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.10 (brs, 1H) 467

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 64 ÓÇT 3- (2,6-dichlorobenciloxy) -5- (3dethylaminomethyl- 1 H-indol-5-yl) - pyridin-2-ylamine 3.23 See example (300 MHz, CDCb) δ 1.13 (t, 6H), 2.64 (q, 4H), 3.88 (s, 2H), 4.66 (brs, 2H), 5.37 (s, 2H), 7.19 (d, J = 1.7 Hz, 1H), 7.26 (m, 1H), 7.37 (m, 5H), 7.86 (s, 1H), 8.00 (d, J = 1.7 Hz, 1H), 8.44 (brs, 1H) 469 1- 65 Terbutil ester del (1- {5- [6 amino-5- (2,6dichloro-benciloxy) pyridin-3-yl] -1 Hindol-3-ylmethyl} (3R) -pyrrolidin-3yl) -carbamico 6.3 See example (300 MHz, CDCb) δ 1.39 (s, 9H), 2.22 (m, 1H), 2.40 (m, 1H), 2.58 (m, 1H), 2.68 (m, 1H ), 2.99 (m, 1H), 3.82 (d, 1H), 3.88 (d, 1H), 4.16 (m, 1H), 4.65 (brs, 2H), 4.81 (m, 1H), 5.41 (s, 2H), 7.17 (d, J = 2.1 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), 7.81 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 8.09 (brs, 1H) 582 1- 66 UL _a k 3- (2,6-dichlorobenciloxy - 5- [3 (2,6-dimethylmorpholin-4-ylmethyl) - 1 H-indol-5-yl] - pyridin-2-ylamine > 20 See example (300 MHz, CDCb) δ 1.13 (d, J = 6.3 Hz, 6H), 1.80 (t, J = 10.7 Hz, 2H), 1.94 (brs, 1H), 2.84 (d, J = 10.5 Hz, 2H), 3.72 (m, 4H), 4.68 (brs, 2H), 5.39 (s, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), 7.89 (s, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.32 (brs, 1H) 511

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 67 Λ Ψ PC ° t N- (1- {5- [6-amino5- (2,6-dichlorobenciloxy) -pyridin3-IIJ-1 H-indol-3ylmethyl} - (3R) pyrrolidin-3-yl) acetamide 1.79 See example (300 MHz, CDCb) δ 1.86 (s, 3H), 2.31 (m, 2H), 2.59 (m, 1H), 2.70 (m, 1H), 2.99 (m, 1H ), 3.82 (d, 1H), 3.90 (d, 1H), 4.42 (m, 1H), 4.68 (brs, 2H), 5.40 (s, 2H), 5.91 (m, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.26 (m, 2H), 7.38 (m, 5H), 7.82 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 8.33 (br s, 1H) 524 1- 68 CX _a 1 - (4— {5— [6 — a mino5- (2,6-dichlorobenciloxy) -pyridin3-IIJ-1 H-indol-3ylmethyl} piperazine-1-yl) ethanone 2.18 See example (300 MHz, CDCb) δ 2.07 (s, 3H), 2.51 (m, 4H), 3.44 (m, 2H), 3.63 (m, 2H), 3.78 (s, 2H), 4.68 (brs, 2H), 5.40 (s, 2H), 7.17 (d, J = 2.2 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), 7.88 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 8.34 (brs, 1H) 524 1- 69 HN — Λ Çf XoM ^NH = F 3- (2-chloro-3,6difluoro-benciloxy) - 5- (1 H-indol-5-yl) - pyridin-2-ylamine See example 386 1- 70 Çj ÇC ú 1- (4- {5- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -1Hindol-3-ylmethyl} piperazine-1yl) ethanone 0.8 See example (300 MHz, CDCb) δ 2.08 (s, 3H), 2.49 (m, 4H), 3.48 (m, 2H), 3.61 (m, 2H), 3.80 (s, 2H), 4.68 (s, 2H), 5.30 (s, 2H), 7.02 (m, 1H), 7.20 (m, 2H) , 7.41 (m, 3H), 7.89 (s, 1H), 8.06 (s, 1H), 8.63 (s, 1H) 526 1- 71 τ 'X ^ O-Í ^ N <jA _to NH, 3- (2-chloro-3,6difluoro-benciloxy) 5- [3 (2,6-dimethylmorpholin-4-ylmethyl) - 1 H-indol-5-yl] - pyridin-2-ylamine 2.71 See example (300 MHz, CDCb) δ 1.37 (d, 6H), 1.92 (m, 2H), 2.95 (m, 2H), 3.87 (m, 4H), 4.68 (s, 2H), 5.34 (s, 2H), 7.08 (m, 1H), 7.27 (m, 2H), 7.48 (m, 3H), 7.89 (s, 1H), 7.98 (s, 1H), 8.21 (br s, 1H) 513

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 72 jojT-y N- (1- {5- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -1Hindol-3-ylmethyl} (3S) -pyrrolidin-3yl) -acetamide 0.95 See example (300 MHz, CDCb) δ 1.71 (m, 1H), 1.81 (s, 3H), 2.31 (m, 2H), 2.48 (m, 1H), 2.79 (m, 2H ), 3.11 (m, 1H), 3.98 (m, 2H), 4.68 (s, 2H), 5.31 (s, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.45 (m, 4H), 7.86 (s, 1H), 7.98 (s, 1H), 8.38 (s, 1H) 526 1- 73 hn- ^ 3- (2-chloro-3,6difluoro-benciloxy) 5- (3-piperidin-1 ylmethyl) -1 H-indol5-yl) -pyridin-2ylamine 0.74 See example (300 MHz, CDCb) δ 1.84 (m, 2H), 1.64 (m, 4H), 2.56 (m, 4H), 3.80 (s, 2H), 4.68 (s, 2H), 5.30 (s, 2H), 7.08 (m, 1H), 7.20 (m, 2H), 7.45 (m, 3H), 7.86 (s, 1H), 7.89 (s, 1H), 8.49 (br s, 1H) 483 1- 74 1 Xt Ιίτ ' ⁰ τ> ΙγΛ _α NHj 3- (2-chloro-3,6difluoro-benciloxy) 5- (3-morpholin-4ylmethyl-1 H-indole-5yl) -pyridin-2ylamine 1.4 See example (300 MHz, CDCb) δ 2.72 (m, 4H), 3.80 (m, 6H), 4.70 (s, 2H), 5.33 (d, 2H), 7.07 (m, 1H ), 7.20 (m, 1H), 7.35- 7.55 (m, 4H), 7.86 (s, 1H), 8.00 (d, 1H), 8.23 (s, 1H) 485 1- 75 rui F 3- (2-chloro-3,6difluoro-benciloxy) 5- (3-pyrrolidin-1 ylmethyl-1 H-indole-5yl) -pyridin-2ylamine 0.7 See example (300 MHz, CDCb) δ 1.86 (m, 4H), 2.79 (m, 4H), 4.01 (s, 2H), 4.63 (s, 2H), 5.30 (d, 2H), 7.05 (m, 1H), 7.18 (m, 1H), 7.30-7.60 (m, 4H), 7.80 (s, 1H), 8.00 (d, 1H), 8.64 (s, 1H) 469 1- 76 Ethyl ester of 5- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-11) -1 H-indole-2carboxylic acid > 20 See example (400 MHz, DMSO- de) δ 1.34 (t, 3H), 4.34 (m, 2H), 5.34 (s, 2H), 5.58 (s, 2H), 7.16 (s, 1H), 7.52 (m, 2H), 7.84 (d, 2H), 11.84 (s, 1H) 456

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 77 VoH çr T ó ^ΝΗ > 5- [6-amino5- (2,6-dichlorobenciloxy) -pyridin- acid 3-111-1 H-indole-2carboxylic 1.62 See example (400 MHz, DMSO- de) δ 5.46 (s, 2H), 5.53 (s, 2H), 6.66 (s, 1H), 7.33 (d, 1H), 7.44 (m , 2H), 7.54 (m, 3H), 7.72 (s, 1H), 7.86 (s, 1H), 11.12 (s, 1H) 428 1- 78 ο Λ ~ \ / \ / ¹ UN- / σ άτι {5- [6-amino-5 (2,6-dichlorobenciloxy) -pyridin3-111-1 H-indol-2-yl} (4-methyl-piperazin-1-yl) -methanone 0.18 See example (400 MHz, DMSO- de) δ 2.21 (s, 3H), 2.36 (m, 4H), 3.74 (m, 4H), 5.35 (s, 2H), 5.53 (s, 2H), 6.78 (s, 1H), 7.50 (m, 6H), 7.81 (s, 1H), 7.88 (s, 1H), 11.56 (s, 1H) 510 1- 79 Çj Jl Δ <V * ^oZ T ÇA, ΝΗ, {5- [6-amino-5 (2,6-dichlorobenciloxy) - pyridin3-111-1 H-indol-2-yl} [(3R) -3-dimethylamino-pyrrolidin-1 yl] -methanone 0.18 See example (400 MHz, DMSO- de) δ 1.80 (m, 1H), 2.12 (m, 1H), 2.21 (s, 6H), 2.74 (m, 1H), 3.25 (m , 1H), 3.53 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 5.36 (s, 2H), 5.54 (s, 2H), 6 , 98 (s, 1H), 7.46 (m, 3H), 7.56 (m, 3H), 7.86 (m, 2H), 11.53 (s, 1H) 524 1- 80 {5- [6-amino-5 (2,6-dichlorobenciloxy) - pyridin3-111-1 H-indol-2-yl} [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin- 1-il] -methanone 0.079 See example (400 MHz, DMSO- de) δ 1.80 (m, 1H), 2.12 (m, 1H), 2.21 (s, 6H), 2.74 (m, 1H), 3.25 (m , 1H), 3.53 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 5.36 (s, 2H), 5.54 (s, 2H), 6 , 98 (s, 1H), 7.46 (m, 3H), 7.56 (m, 3H), 7.86 (m, 2H), 11.53 (s, 1H) 524 1- 81 φ U Âf ^ o-Ç ¹ Ά, 5- [6-amino5- (2,6-dichlorobenciloxy) -pyridin- acid 3-111-1 H-indole-2-carboxylic (2pyrrolidin-1-yl-ethyl) amide 1.2 See example (400 MHz, DMSO- de) δ 1.66 (m, 4H), 2.51 (m, 4H), 2.58 (t, 2H), 3.39 (m, 2H), 7.11 (s , 1H), 7.45 (m, 2H), 7.55 (m, 3H), 7.60 (m, 1H), 7.82 (s, 1H), 7.88 (s, 1H), 8.45 (t, 1H), 11.56 (s, 1H) 524

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 82 Ux _o 5- [6-amino5- (2,6-dichlorobenciloxy) -pyridin- acid 3-IL-1H-indole-2-carboxylic (2morpholin-4-yl-ethyl) amide 1.8 See example (400 MHz, DMSO- de) δ 2.41 (m, 6H), 3.39 (m, 2H), 3.58 (m, 4H), 7.11 (s, 1H), 7.45 (m, 2H), 7.55 (m, 4H), 7.82 (s, 1H), 7.88 (s, 1H), 8.42 (t, 1H), 11.52 (s, 1H) 540 1- 83 Λτ ^ 'τ kA _o «s Terbutil ester del (1- {5- [6 amino-5- (2,6dichloro-benciloxy) pyridin-3-yl] -1 Hindol-2-carbonyl} (3S) -pyrrolidin-3yl) -carbamic 5 See example (400 MHz, DMSO- de) δ 1.38 (s, 9H), 1.64 (m, 1H), 1.98 (m, 2H), 3.18 (m, 2H), 3.78 (m, 2H), 5.37 (s, 2H), 5.53 (s, 2H) , 6.92 (m, 1H), 7.26 (m, 1H), 7.48 (m, 2H), 7.56 (m, 3H), 7.61 (m, 1H), 7.86 ( m, 2H), 11.52 (s, 1H) 596 1- 84 JL ^ JU Ul _cl MK _a {5- [6-amino-5 (2,6-dichlorobenciloxy) - pyridin3-IL-1 H-indol-2-yl} [(3S) -3- Aminopyrrolidin-1-yl] methanone 0.14 See example (400 MHz, DMSO- de) δ 2.20 (m, 2H), 2.68 (m, 1H), 3.84 (m, 4H), 5.56 (s, 2H), 7.52 (m, 6H), 7.94 (m, 5H), 8.62 (m, 2H) 496 1- 85 \ A NH, 5- [6-amino5- (2,6-dichlorobenciloxy) acid - pyridin- 3-IL-1-H-indole-2-carboxylic (2-hydroxy-3-pyrrolidin-1-ylpropyl) -amide 0.7 See example (400 MHz, DMSO- de) δ 1.67 (m, 4H), 2.37 (m, 1H), 2.52 (m, 1H), 3.31 (m, 1H), 3.62 (m, 4H), 3.46 (m, 1H), 3.76 (m, 1H), 5.38 (s, 2H), 5.52 (s, 2H), 7.14 (s, 1H), 7.46 (m, 2H), 7.56 (m, 4H), 7.86 (m, 2H), 8.48 (t, 1H), 11.58 (s, 1H) 554 1- 86 OH 4 nh ₂ 4- (6-amino-5benciloxy-pyridin3-yl) -phenol 8.7 See example (400 MHz, DMSO- de) δ 9.4 (s, 1H), 7.74 (d, J = 2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7, 38 (m, 4H), 7.32 (m, 2H), 6.8 (d, J = 7.2 Hz, 2H), 5.69 (s, 2H), 5.22 (s, 2H) 293

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 87 NHj 3-benciloxy-5phenyl-pyridin-2ylamine See example (400 MHz, DMSO- de) δ 7.84 (d, 1H), 7.56 (d, 2H), 7.51 (d, 2H), 7.38 (m, 5H), 7.31 (t, 1H), 7.25 (t, 1H), 5.83 (brs, 2H), 5.24 (s, 2H) 277 1- 88 NHj 3- (3-methoxybenciloxy) -5-phenylpyridin-2-ylamine See example (400 MHz, DMSO- de) δ 7.85 (d, 1H), 7.56 (m, 2H), 7.38 (m, 3H), 7.28 (m, 2H), 7.08 (m, 2H), 6.86 (m, 1H), 5.84 (brs, 2H) , 5.21 (s, 2H), 3.75 (s, 3H) 307 1- 89 nh. 3- (2-chloro-4-fluorbenciloxy) -5-phenylpyridin-2-ylamine 17 See example (400 MHz, DMSO- de) δ 7.88 (s, 1H) 7.79 (m, 1H), 7.59 (m, 2H), 7.51 (dd, 1H), 7.40 (m, 3H), 7.27 (m, 2H), 5.84 (s, 2H), 5.24 (s, 2H) 329 1- 90 0 Q- ^to A 3- (2-chlorobenciloxy) -5-phenylpyridin-2-ylamine 48% a 20 uM See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.73 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.38 (m, 5H), 7.26 (m, 1H), 5.57 (s, 2H), 5.30 (s, 2H) 311 1- 91 ° - €> ^to A <0 ^ NH, 3- (2,5-dichlorobenciloxy) -5-phenylpyridin-2-ylamine 48% a 20 uM See example (400 MHz, DMSO- de) δ 7.89 (d, 1H), 7.85 (d, 1H), 7.59 (m, 2H), 7.53 (d, 1H), 7.46 (d, 1H), 7.39 (m, 3H), 7.26 (m, 1H), 5.95 (s, 2H), 5.30 (s, 2H) 345 I- 92 0 "H. 3- (2-chloro-5trifluoromethylbenciloxy) -5-phenylpyridin-2-ylamine > 20 See example (400 MHz, DMSO- de) δ 8.16 (s, 1H), 7.89 (d, 1H), 7.76 (d, 2H), 7.59 (m, 2H), 7.48 (d , 1H), 7.39 (m, 2H), 7.26 (m, 1H), 5.90 (s, 2H), 5.36 (s, 2H) 379 I- 93 ^a > = \ Q <oV NHj 3- (2,4-dichloro-5fluor-benciloxy) -5phenyl-pyridin-2ylamine > 20 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.88 (m, 2H), 7.60 (m, 2H), 7.44 (d, 1H), 7.39 (m, 2H), 7.26 (m, 1H), 6.01 (s, 2H), 5.24 (s, 2H) 364

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 94 , to Gr ^a rT HHj 3- (2-chloro-3trifluoromethylbenciloxy) -5-phenylpyridin-2-ylamine > 20 See example (400 MHz, DMSO- de) δ 8.10 (d, 1H), 7.89 (d, 1H), 7.85 (m, 1H), 7.60 (m, 3H), 7.45 (d, 1H), 7.39 (m, 2H), 7.26 (m, 1H), 5.93 (s, 2H), 5.37 (s, 2H) 379 1- 95 NHj 3- (2-chloro-3,6difluoro-benciloxy) 5-phenyl-pyridin-2ylamine 0.64 See example (400 MHz, DMSO- de) δ 7.89 (d, 1H), 7.57 (m, 4H), 7.40 (m, 3H), 7.26 (m, 1H), 5.72 (s, 2H), 5.28 (s, 2H) 347 1- 96 li ^ ú ^Q \ u Ψ QX NK 3- (3,4-dichlorobenciloxy) -5-phenylpyridin-2-ylamine 16.2 See example (400 MHz, DMSO- de) δ 7.86 (d, 1H), 7.84 (d, 1H), 7.65 (m, 1H), 7.67 (m, 3H) 7.39 (m, 3H), 7.26 (m, 1H), 5.96 (s, 2H), 5.24 (s, 2H); MS m / z 345 [M + 1], 345 1- 97 0 Q Λ, _{f =} / V PS NH, 2- (2-amino-5-phenyl-pyridin-3yloxymethyl) benzonitrile 12.2 See example (400 MHz, DMSO- de) δ 7.90 (dd, 2H), 7.82 (d, 1H), 7.75 (m, 1H), 7.56 (m, 3H), 7.48 (d , 1H), 7.40 (m, 2H), 7.26 (m, 1H), 5.85 (s, 2H), 5.39 (s, 2H) 302 1- 98 O Λ \ s ^ Ç NHj 3- (2-chloro-6-fluoro3-methyl-benciloxy) 5-phenyl-pyridin-2ylamine 7.6 See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.61 (m, 2H), 7.53 (d, 1H), 7.43 (m, 3H), 7.25 (m, 2H), 5.65 (s, 2H), 5.27 (s, 2H), 2.34 (s, 3H) 342 1- 99 9 ^f o ^f yV ° V <A. _f nh, 5-phenyl-3- (2,3,6trifluoro-benciloxy) pyridin-2-ylamine 3.9 See example (400 MHz, DMSO- de) δ 7.89 (d, 1H), 7.61 (m, 3H), 7.52 (d, 1H), 7.40 (m, 2H), 7.25 (m , 2H), 5.75 (s, 2H), 5.26 (s, 2H) 331 1- 100 U- _F Nri, 3- (2,6-diflúorbenciloxy) -5-phenylpyridin-2-ylamine 9.3 See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.61 (m, 2H), 7.51 (m, 2H), 7.40 (m, 2H), 7.26 (m, 1H), 7.18 (m, 2H), 5.69 (s, 2H), 5.23 (s, 2h) 314

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 101 ° ΊΓ 3- (2,6-diflúor-3methyl-bencilóxi) -5phenyl-pyridin-2ylamine 12 See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.60 (m, 2H), 7.51 (d, 1H), 7.40 (m, 3H), 7.27 (m , 1H), 7.07 (m, 1H), 5.68 (s, 2H), 6.21 (s, 2H) 328 I- 102 O XX / X 3- (3-chloro-2,6difluoro-bencilóxi) 5-phenyl-pyridin-2ylamine 9.6 See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.74 (m, 1H), 7.61 (m, 2H), 7.51 (d, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 5.76 (s, 2H), 5.26 (s, 2H) 347 I- 103 Q (ΧΎ 3- (2-chloro-6-fluorbenciloxy) -5-phenylpyridin-2-ylamine 7.91 See example (400 MHz, DMSO- de) δ 7.88 (d, 1H), 7.61 (m, 2H), 7.52 (d, 1H), 7.49 (m, 1H), 7.40 (m , 3H), 7.30 (m, 2H), 5.67 (s, 2H), 5.27 (s, 2H) 329 I- 104 THE NH, 3- (3-fluorine- 4- methoxy-benciloxy) 5-phenyl-pyridin-2-amine 15 See example (400 MHz, DMSO- de) δ 7.84 (d, 1 H), 7.56 (m, 1H), 7.43 (d, 1H), 7.38 (m, 3H), 7.26 (m, 2H), 7.10 (m, 2H), 5.58 (s, 2H), 5.15 (s, 2H) 325 I- 105 ff H ° Ks? ^NH i N- [3- (2-amino-5-phenyl-pyridin-3yloxymethyl) -phenyl] methanesulfonamide > 20 See example (400 MHz, DMSO- de) δ 9.76 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.57 (d, 2H), 7.38 (m, 5H), 7.28 (m, 2H), 7.15 (d, 1H), 5.85 (brs, 2H), 5.22 (s, 2H), 2.96 (s, 3H) 370 I- 106 _z the JISK k 5- [4- (2-morpholin-4yl-ethoxy) -phenyl] -3- (3-nitro-benciloxy) pyridin-2-ylamine 12.6 See example (DMSO- de) δ 2.50 (m, 4H), 2.69 (m, 2H), 3.57 (t, 4H), 4.09 (t, 2H), 5.37 (s, 2H), 5.85 (s, 2H), 6.96 (d, 2H), 7.38 (d, 1H), 7.48 (d, 2H), 7.69 (t, 1H), 7.81 (d, 1H), 8.01 (m, 1H), 8.17 (m, 1H), 8.36 (m, 1H) 451

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 107 z ° NO, JÍ1 OK 5- [4- (2-morpholin-4yl-ethoxy) -phenyl] -3 (naphthalene-1ylmethoxy) -pyridin-2ylamine 7.7 See example (DMSO- de) δ 2.50 (m, 4H), 2.69 (t, 2H), 3.57 (t, 4H), 4.10 (t, 2H), 5.66 (s, 2H), 5.67 (s, 2H), 6.97 (d, 2H), 7.49-7.61 (m, 5H), 7.78- 7.82 (m, 2H), 7.88-7.98 (m, 2H), 8.20 (dd, 1H) 456 I- 108 _f o Q ^F Or 3- (2-chloro-3,6difluoro-benciloxy) 5- [4- (2-morpholin-4yl-ethoxy) phenyl] pyridin-2ylamine 0.21 See example (400 MHz, CDCb) δ 2.60 (m, 4H), 2.83 (t, 2H), 3.74 (t, 4H), 4.16 (t, 2H), 4.63 (s, 2H), 5.27 (d, 2H), 6.98 (d, 2H), 7.02-7.10 (m, 1H), 7.16-7.22 (m, 1H), 7.30 (2, 2H), 7.44 (d, 2H), 7.91 (d, 1H) 476 I- 109 The Q li A- 2- {2-amino-5- [4 (2-morpholin-4-yloxy) -phenyl] pyridin-3-yloxy} -N (4-isopropyl-phenyl) 2-phenyl-acetamide > 20 See example (400 MHz, DMSO- de) δ 1.15 (d, 6H), 2.50 (m, 4H), 2.68 (m, 2H), 2.77-2.89 (m, 1H), 3.57 (t, 6H), 4.08 (t, 2H), 6.15 (s, 1H), 6.20 (s, 2H), 6.93 (d, 2H), 7.17 (d, 1H), 7.307.44 (m, 3H), 7.48 (d, 2H), 7.68 (d, 2H), 7.79 (d, 1H) 568 I- 110 0 \ íS NH, 3- (5-chlorobenzo [b] thiophen-3ylmethoxy) -5- [4- (2morpholin-4-yletoxy) -phenyl] pyridin-2-ylamine 2.4 See example (400 MHz, DMSO- de) δ 2.50 (m, 4H), 2.70 (m, 2H), 3.58 (t, 4H), 4.11 (t, 2H), 5.46 (s , 2H), 5.82 (s, 2H), 6.98 (d, 2H), 7.43 (dd, 1H), 7.50- 7.66 (m, 3H), 7.80 (d, 1H), 8.05 (d, 1H), 6.11 (d, 1H), 8.16 (s, 1H) 496.5

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 111 0 Λ / Uyf NH _S 4 {4- [6-amino-5- (4fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 1.51 See example (400 MHz, DMSO- de) δ 7.94 (s, 2H), 7.71 (m, 4H), 7.44 (m, 3H), 5.92 (s, 2H), 5.36 (s, 2H), 4.21 (m, 1H), 3.52 (m, 2H), 2.69 (m, 5H), 1.96 (m, 2H), 1.84 (m, 3H), 1.66 (m, 4H) 543 I- 112 X 0 {4- [6-amino-5- (2fluor-6trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.15 See example (400 MHz, DMSO- de) δ 7.94 (s, 1H), 7.69 (m, 5H), 7.59 (s, 1H), 7.50 (m, 2H), 5.72 (s , 2H), 5.26 (s, 2H), 4.16 (m, 1H), 3.47 (m, 2H), 2.63 (m, 5H), 1.96 (m, 2H), 1 .86 (m, 3H), 1.68 (m, 4H) 543 I- 113 X T xç-τ ^F F {4- [6-amino-5- (5fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 1.27 See example (400 MHz, DMSO- de) δ 7.95 (s, 1H), 7.85 (m, 2H), 7.63 (m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 6.04 (s, 2H), 5.36 (s, 2H) , 4.16 (m, 1H), 3.44 (m, 2H), 2.62 (m, 5H), 1.96 (m, 2H), 1.85 (m, 3H), 1.66 (m, 4H) 543 I- 114 X 0 (4- {6-amino-5- [1 (2-trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -methanone 0.33 See example (400 MHz, DMSO- de) δ 7.85 (d, 1H), 7.81 (s, 1H), 7.76 (m, 2H), 7.41 (m, 5H), 7.03 (s, 1H), 6.16 (s, 2H), 5.81 (m, 1H), 4.10 (m, 1H), 3.41 (m, 2H), 2.59 (m, 5H), 1.94 (m, 2H), 1.82 (m, 3H) 1.64 (d, 3H), 1.48 (m, 4H) 539 I- 115 {4- [6-amino-5- (2bromo-benciloxy) pyridin-3-yl] -phenyl} [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -methanone 1.75 See example (400 MHz, DMSO- de) δ 7.74 (s, 1H), 7.68 (m, 3H), 7.45 (m, 5H), 7.31 (m, 1H), 5.92 (s , 2H), 5.25 (s, 2H), 4.16 (m, 1H), 3.43 (m, 2H), 2.62 (m, 5H), 1.94 (m, 2H), 1 82 (m, 3H), 1.65 (m, 4H) 537

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 116 Gs'. ^NH - {4- [6-amino-5- (3fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.025 See example (400 MHz, DMSO- de) δ 7.92 (s, 1 H), 7.66 (m, 4H), 7.46 (m, 4H), 5.89 (s, 2H), 6.39 (s, 2H), 4.19 (m, 1H), 3.50 (m, 2H), 2.54 (m, 5H), 1.95 (m, 2H), 1.83 (m, 3H), 1.64 (m, 4H) 543 I- 117 ^NH * {4- [6-amino-5- (2-chloro-3,6-difluorbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.063 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.69 (d, 2H), 7.58 (m, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 5.81 (s, 2H), 5.29 (s, 2H), 4.35 (m, 1H), 3.5 (d, 2H), 2.87 (d, 2H), 2.71 (d, 2H), 1.72.0 (m, 10H) 527 I- 118 NH, 4- [6-amino-5- (2,6difluoro-benciloxy) pyridin-3-yl] -phenol 3.79 See example (400 MHz, DMSO- de) δ 9.38 (s, 1H), 7.77 (d, J = 2Hz1H), 7.52 (m, 2H), 7.40 (m, 3H), 7.17 (m, 2H), 6.79 (m, 2H), 5.53 (br, s, 2H), 5.20 (s, 2H) 329 I- 119 <Ap NH, 3- (2,6-diflúorbenciloxy) -5- (IHindol-4-yl) -pyridin2-ylamine 5.8 See example (400 MHz, DMSO- de) δ 7.81 (d, J = 2Hz, 1H), 7.51 (m, 3H), 7.45 (d, J = 2Hz, 1H), 7.17 (m, 2H), 6.98 (m, 2H), 5.58 (s, 2H ), 5.21 (s, 2H), 4.10 (t, 2H), 3.57 (t, 4H), 2.69 (t, 2H), 2.48 (t, 4H) 442 I- 120 _z o ô Ar ^ _o Xf ^ ^N <sA. _P »* s 3- (2,6-diflúorbencilóxi) -5- [4- (2morfolin-4-yletoxy) -phenyl] pyridin-2-ylamine See example (400 MHz, DMSO- de) δ 11.18 (s, 1H), 7.86 (d, J = 2Hz, 1H), 7.52 (m, 1H), 7.44 (d, J = 2Hz, 1H), 7.36 (dd, 1H), 7.34 (m, 1H), 7.18 (m, 2H), 7.13 (dd, 1H), 7.02 (dd, 1H), 6.49 (m, 1H), 5, 66 (s, 2H), 5.22 (s, 2H) 352

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 121 NH, 4- [6-amino- 5- (2,6-difluorborboxy) -pyridin- 3-il) -benzoic See example (400 MHz, DMSO- de) δ 12.85 (s, 1H), 7.94 (d, J = 2Hz, 1H), 7.89 (dd, 2H), 7.71 (dd, 2H), 7.55 (d, J = 2Hz, 1H), 7.47 (m, 1H), 7.13 (m, 2H), 5.83 (s, 2H), 5.19 (s, 2H) 357 I- 122 {4- [6-amino-5 (2,6-difluorborboxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 1.21 See example (400 MHz, DMSO- de) δ 7.94 (d, 1H), 7.68 (dd, 2H), 7.56 (m, 1H), 7.51 (m, 3H), 7.18 (m , 2H), 5.79 (s, 2H), 5.29 (s, 2H), 3.48 (m, 1H), 2.65 (m, 4H), 2.48 (d, 2H), 1 86 (m, 10H) 493 I- 123 ΓΛ '* ’ {4- [6-amino-5 (2,6-difluorborboxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 1.36 See example (400 MHz, DMSO- de) δ 7.94 (d, 1H), 7.68 (dd, 2H), 7.56 (m, 1H), 7.51 (m, 3H), 7.18 (m, 2H), 5.78 (s, 2H), 5.24 (s, 2H), 4.6 (m, 1H), 3.5 (m, 2H), 2.52 (d, 4H), 1.86 (m, 10H) 493 I- 124 χι ° ^ Q Apo-Ç NH, Ethyl ester dei {4- [6-amino-5 (2,6-difluoroorbenciloxy) -pyridin3-yl] -phenoxy} acid See example (400 MHz, DMSO- de) δ 7.81 (d, J = 2Hz, 1H), 7.52 (m, 3H), 7.18 (m, 1H), 6.96 (m, 2H), 5 , 70 (br, s, 2H), 5.23 (s, 2H), 4.79 (s, 2H), 2.68 (q, 4H), 1.21 (t, 3H) 415 I- 125 -X o kAp NH, {4- [6 amino-5- (2,6difluoro-benciloxy) pyridin-3-yl] phenoxyacetic acid 14.7 See example (400 MHz, DMSO- de) δ 7.79 (d, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.44 (m, 2H), 7.17 (m, 2H), 7.05 (m, 2H), 5.55 (br, s, 2H), 5.21 (s, 2H), 4.25 (s, 2H) 387

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 126 2- {4- [6-amino-5 (2,6-difluorborboxy) -pyridin3-yl] -phenoxy} -1 [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -ethanone 3.58 See example (400 MHz, DMSO- de) δ 7.81 (d, 1H), 7.51 (m, 3H), 7.45 (d, 1H), 7.18 (m, 2H), 6.80 (m , 2H), 5.65 (s, 2H), 5.22 (s, 2H), 4.80 (dd, 2H), 4.29 (m, 1H), 3.53 (m, 2H), 3 , 20 (m, 4H), 1.93 (m, 10H) 523 I- 127 P" F / -Γ * H / í 2- {4- [6-amino-5 (2,6-difluorborboxy) -pyridin3-yl] -phenoxy} -1 [(2S) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -ethanone 5.43 See example (400 MHz, DMSO- de) δ 7.81 (d, 1H), 7.52 (m, 3H), 7.46 (d, 1H), 7.18 (m, 2H), 7.00 (m , 2H), 5.66 (s, 2H), 5.22 (s, 2H), 4.80 (dd, 2H), 4.60 (m, 1H), 3.53 (m, 2H), 3 , 19 (m, 4H), 1.96 (m, 10H) 523 I- 128 OH Ô AV LA _a nh ₂ 4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -phenol 3.99 See example (400 MHz, DMSO- de) δ 9.38 (s, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.42 (m, 4H), 7.39 (m , 1H), 6.80 (m, 2H), 5.50 (s, 2H), 5.24 (s, 2H) 345 I- 129 í 4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -phenol 19 See example (DMSO- de) δ 5.21 (s, 2H), 5.67 (s, 2H), 6.80 (d, 2H), 7.26 (t, 1H), 7.34 (s, 1H), 7.41 (d, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 9.38 (s, 1H) 345 I- 130 OH Q f7 ο τ _ο ΛΑ _α nh, 4- [6-amino-5- (2,4dichloro-benciloxy) pyridin-3-yl] -phenol 9 /> 20 See example (DMSO- de) δ 5.21 (s, 2H), 5.71 (s, 2H), 6.81 (d, 2H), 7.40 (m, 5H), 7.74 (m, 2H), 9.38 (s, 1H) 361 I- 131 X 2- [2-amino-5- (4-hydroxy-phenyl) pyridin-3yloxymethyl]] benzonitrile 19 See example (DMSO-de) δ 5.35 (s, 2H), 5.68 (s, 2H), 6.77 (d, 2H), 7.41 (m, 3H), 7.54 (t, 1H), 7.78 (m, 3H), 7.92 (d, 1H), 9.38 (s, 1H) 318

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 132 J Η, 4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenol 3.67 See example (400 MHz, DMSO- de) δ 5.32 (s, 2H), 5.68 (s, 2H), 6.78 (d, 2H), 7.26 (s, 1H), 7.36 (d, 2H), 7.57 (t, 1H), 7.72 (t, 1H), 7.78 (m, 2H), 7.86 (m, 1H), 9.38 (s, 1H) 361 I- 133 OH nh, 4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -phenol 13.8 See example (DMSO-de) δ 5.25 (s, 2H), 5.69 (s, 2H), 6.78 (d, 2H), 7.38 (m, 5H), 7.50 (m, 1H) , 7.71 (m, 1H), 7.78 (s, 1H), 9.38 (s, 1H) 326 I- 134 4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -phenol 4 See example (DMSO-de) δ 1.26 (s, 9H), 5.16 (s, 2H), 5.63 (s, 2H), 6.78 (d, 2H), 7.40 (m, 7H), 7.72 (s, 1H), 9.36 (s, 1H) 349 I- 135 A 0 Λ ítr ' ⁰ ' T ^> kA _CN nh. N- {4- [6-amino-5 (2-cyanobenciloxy) -pyridin3-yl] phenylmethanesulfone mida 4.18 See example (DMSO- de) δ 2.98 (s, 3H), 5.36 (s, 2H), 5.82 (s, 2H), 7.24 (d, 2H), 7.42 (s, 1H), 7.58 (m, 3H), 7.75 (t, 1H), 7.89 (m, 3H), 9.70 (s, 1H) 393 I- 136 0 hh, 0 2- [2-amino-5- (4-methanesulfonylamine-phenyl) pyridin-3yloxymethyl] benzamide > 20 See example (DMSO- de) δ 2.88 (s, 3H), 5.37 (s, 2H), 5.75 (s, 2H), 7.15 (d, 2H), 7.30 (s, 1H), 7.48 (m, 6H), 7.20 (d, 1H), 7.80 (s, 1H), 7.90 (s, 1H) 413 I- 137 The rv ° j 2- [2-Amino- acid 5- (4methanesulfonylamine-phenyl) pyridin-3yloxymethyl] benzoyl > 20 See example (DMSO-de) δ 3.00 (s, 3H), 5.65 (s, 2H), 7.26 (d, 2H), 7.47 (m, 3H), 7.60 (m, 4H) , 7.72 (m, 1H), 7.82 (s, 1H), 7.94 (d, 1H), 9.84 (s, 1H) 414

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 138 ff ' 9 N- (4- {6-amino-5 [2- (4-methylpiperazine-1carbonyl) benciloxy] -pyridin3-yl} phenyl) methanesulfone mida > 20 See example (DMSO- de) δ 2.08 (s, 3H), 2.26 (m, 2H), 2.96 (s, 3H), 3.15 (m, 2H), 3.36 (m, 2H), 3.59 (m, 2H), 5.17 (br s, 2H), 5.78 (s, 2H), 7.23 (d, 2H), 7.28 (m, 1H), 7.36 (s, 1H), 7.43 (m, 2H), 7.57 (m, 4H), 7.84 (s, 1H) 496 I- 139 HbT ^ * o NHj ^ .NH 2- [2-amino-5- (4methanesulfonylamine-phenyl) pyridin-3yloxymethyl] -N- (2hydroxy-ethyl) benzamide > 20 See example (DMSO- de) δ 2.96 (s, 3H), 3.28 (m, 2H), 3.46 (m, 2H), 4.70 (s, 1H), 5.30 (s, 2H), 5.78 (s, 2H), 7.23 (d, 2H), 7.32 (s, 1H), 7.39 (m, 1H), 7.47 (m, 2H), 7.53 (m, 2H), 7.62 (d, 1H), 7.83 (s, 1H), 8.37 (t, 1H), 9.72 (brs, 1H) 457 I- 140 S> look Ah, 2- [2-amino-5- (4-methanesulfonylamine-phenyl) pyridin-3yloxymethyl] -Nisobutylbenzamide > 20 See example (DMSO-de) δ 0.84 (d, 6H), 1.78 (m, 1H), 2.82 (s, 3H), 3.03 (t, 2H), 5.28 (s, 2H), 5.72 (s, 2H), 7.12 (d, 2H), 7.24 (s, 1H), 7.42 (m, 5H), 7.62 (d, 1H), 7.79 (s, 1H), 8.41 (t, 1H), 9.68 (s, 1H) 469 I- 141 0 ^, 0 1 3rd Hello nh, 1 4- [6-amino- 5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -benzoic See example (400 MHz, DMSO- de) δ 5.25 (s, 2H, CH ₂ ), 5.82 (brs, 2H, NH2), 6.30 - 8.00 (multiples, 9H, aromatic) 373 I- 142 oJÓ 0 ίιΓ NH, {4- [6-amino-5- (2chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 0.63 See example (300 MHz, CDCb) δ 7.96 (d, 1H), 7.57 (m, 4H), 7.10 (m, 3H), 7.04 (t, 1H), 5.30 (s, 2H), 4.83 (s, 2H), 4.45 (m, 1H), 3.40 (m, 2H), 2.90 (m, 4H), 2.2-1.5 (m, 10H) 509

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 143 p P JO It ⁰ 1 {4- [6-amino-5- (2chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 13 See example (300 MHz, CDCb) δ 7.96 (d, 1H), 7.57 (m, 4H), 7.10 (m, 3H), 7.04 (t, 1H), 5.30 (s, 2H), 4.83 (s, 2H), 4.45 (m, 1H), 3.40 (m, 2H), 2.90 (m, 4H), 2.2-1.5 (m, 10H) 509 I- 144 ₀ J ΝΗ; {4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 1.7 See example (300 MHz, CDCb) δ 7.94 (s, 1H), 7.58 (m, 4H), 7.36 (m, 3H), 7.05 (t, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 3.9 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H) , 3.0 (m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.8 (m, 2H) 470 I- 145 . ίΤ 0 .ví ÚAf ΝΗ, {4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 0.63 See example 441 I- 146 Ρ ίΊ. 0Ç ° k {4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl] -methanone 1.94 See example (300 MHz, CDCb) δ 7.93 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.28 (m, 3H), 7.07 (t, J = 8.8 Hz), 5.30 (s, 2H), 5.05 (brs, 2H), 3.75 (m, 4H), 2.48 (m, 4H), 2.34 (s, 3H) 455 I- 147 pT πι ΧΑρ ΝΗ, 1- (4- {4- [6-amino- 5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -benzoyl} piperazin-1 -II] ethanone 1.45 See example (300 MHz, CDCb) δ 7.91 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.35 (m, 3H), 7.08 (t, J = 8.2 Hz), 5.32 (brs, 2H), 3.60 (m, 8H), 2.14 (s, 3H) 484

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 148 CCu 4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -N- (2morpholin-4-yl-ethyl) benzamide 6.4 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.30 (m, 2H), 7.24 (d, J = 1.7 Hz, 1H), 7.08 (m, 1H), 6.95 (brt, 1H), 5, 32 (s, 2H), 5.06 (brs, 2H), 3.82 (m, 4H), 3.64 (m, 2H), 2.76 (m, 2H), 2.65 (m, 4H) 485 I- 149 0 4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 5.6 See example (300 MHz, CDCb) δ 8.02 (brt, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 1.7 Hz, 1H), 7.30 (m, 2H), 7.08 (m, 1H), 6.95 (br t, 1H), 5.32 (s, 2H), 5.10 (brs, 2H), 3.78 (m, 4H), 3.62 (m, 2H), 2.64 (m, 6H), 1.87 (m, 2H) 499 I- 150 O ^ OH 0 (VIDEO 4- [6-amino5- (2-chlorobenciloxy) -pyridin3-yl] -benzoic acid See example (400 MHz, DMSO- de) δ 5.30 (s, 2H, CH2), 5.95 (brs, 2H, NH2), 7.35 - 7.95 (multiples, 10H, aromatic), 353 (M- 1) I- 151 £ dr-V {4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -phenyl} [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl] -methanone 0.87 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.6 Hz, 1H), 7.52 (m, 6H), 7.25 (m, 2H), 7.21 (d, J = 1.6 Hz, 1H), 5.26 (s, 2H), 4.88 (brs, 2H), 4.32 (m, 1H), 3 , 52 (m, 2H), 2.89 (m, 4H), 2.2- 1.5 (m, 10H), 491

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 152 p ₀ b 0 o ' ⁴ *! NM » {4- [6-amino-5- (2-chloro-6-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 2.3 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.6 Hz, 1H), 7.52 (m, 6H), 7.25 (m, 2H), 7.21 (d, J = 1.6 Hz, 1H), 5.26 (s, 2H), 4.88 (brs, 2H), 4.32 (m, 1H), 3.52 (m, 2H), 2.89 (m, 4H), 2.2- 1.5 (m, 10H), MS m / z 491 [M + 1] 491 I- 153 x- _o x ^ NHj {4- [6-amino-5- (2 chloro-benciloxy) pyridin-3-yl] -phenyl} [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 12.7 See example (300 MHz, CDCb) δ 7.95 (s, 1H), 7.53 (m, 6H), 7.33 (m, 2H), 7.27 (s, 1H), 5.26 (s, 2H), 4.94 (brs, 2H), 3.90 (m, 1H), 3.60 (m, 2H), 3.45 (m, 1H), 2.85 (m, 1H), 2.32 (s , 3H), 2.23 (s, 3H), 1.89 (m, 2H) 451 I- 154 LJ «n {4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -phenyl} [(3S) -3-aminopyrrolidin-1 -II] methanone 1.44 See example 423 I- 155 rr ° 0 Now {4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -phenyl} (4-pyrrolidin-1 -IIpiperidin-1 -II) methanone 1.5 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz, 1H), 7.47 (m, 6H), 7.32 (m, 2H), 7.21 (d, J = 1.8 Hz, 1H), 5.26 (s, 2H), 4.86 (brs, 2H), 3.95 (m, 4H), 2.55 (m, 4H), 2.30 (m, 1H), 1.95 (m, 2H), 1.76 (m, 4H), 1.52 (m, 2H), 491 I- 156 □ σ 0 HH, {4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -phenyl} (4-methyl-piperazin1-yl) -methanone 2.1 See example (300 MHz, CDCb) δ 7.94 (d, J = 1.8 Hz, 1H), 7.49 (m, 6H), 7.32 (m, 2H), 7.21 (d, J = 1.8 Hz, 1H), 5.27 (s, 2H), 4.00 (brs, 2H), 3.80 (m, 4H), 2.50 (m, 4H), 2.35 (s, 3H) 437

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 157 the 0 0 '1- (4- {4- [6-amino5- (2-chloro-benciloxy) -pyridin-3-yl] benzoyl} piperazin-1 -II) ethanone 3.8 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.51 (m, 6H), 7.33 (m, 2H), 7.21 (d, J = 1.8 Hz, 1H), 5.27 (s, 2H), 4.94 ( brs, 2H), 3.65 (m, 8H), 2.14 (s, 3H) 465 I- 158 A ^ - ^ A ^ u 4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) benzamide 8.9 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.51 (m, 1H), 7.43 (m, 1H), 7.34 (m, 2H), 7.24 (d, J = 1.8 Hz, 1H), 7, 01 (brt, 1H), 5.27 (d, 2H), 5.18 (brs, 2H), 3.77 (m, 4H), 3.61 (m, 2H), 3.25 (m, 2H), 2.70 (m, 2H), 2.60 (m, 4H) 467 I- 159 O 0 Ar ^ Ç MH, 4- [6-amino-5- (2-chloro-benciloxy) pyridin-3-yl] -N- (3-morpholin-4-ylpropyl) -benzamide 4.5 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.51 (m, 2H), 7.43 (m, 1H), 7.34 (m, 2H), 7.24 (d, J = 1.8 Hz, 1H), 5.27 (s, 2H), 4.97 (brs, 2H), 3.75 (m, 4H), 3.59 (m, 2H), 3.25 (m, 2H), 2.57 (m, 4H), 1.83 (m, 2H), 481 I- 160 O ^ _Z OH òA 4- [6-amino5- (2-cyano-benciloxy) -pyridin-3-yl] benzoic acid See example (400 MHz, DMSO- de) δ 5.35 (s, 2H, CH2), 5.95 (brs, 2H, NH2), 7.50 - 8.00 (multiples, 10H, Aromatic) 346

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 161 O CN u 2- {2-amino-5- [4 ((2H) -2-pyrrolidin1 -ylmethylpyrrolidine-1 carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile 1.2 See example (300 MHz, CDCb) δ 7.99 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), 7.24 (d, J = 1.6 Hz, 1H), 5.35 (s, 2H), 4.88 (brs, 2H), 4.46 (m, 1H), 3.52 (m, 2H), 3.24 (m, 4H), 2.2-1.5 (m, 10H) 482 I- 162 ₀ b NH, 2- {2-amino-5- [4 ((2S) -2-pyrrolidin1 -ylmethylpyrrolidine-1 carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile 2 See example Ή NMR (300 MHz, CDCb) δ 7.99 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), 7.24 (d, J = 1.6 Hz, 1H), 5.35 (s, 2H), 4.88 (brs, 2H), 4.46 (m, 1H), 3.52 (m, 2H), 3.24 (m, 4H), 2.2-1.5 (m, 10H), 482 I- 163 l 0? ^No. 2nd CP 2- {2-amino-5- [4 ((3S) -3dimethylaminopyrrolidine-1 carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile > 20 See example (300 MHz, CDCb) δ 7.98 (s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.50 (m, 6H), 7.26 (s, 1H), 5.36 (s, 2H), 4.99 (brs, 2H), 3.90 (m, 1H), 3.60 (m, 2H), 3.45 (m, 1H), 2.85 (m , 1H), 2.32 (s, 3H), 2.23 (s, 3H), 1.89 (m, 2H) 442 I- 164 CN A <-o'V ⁿ NH, 2- {2-amino-5- [4 ((3S) -3-aminopyrrolidine-1 carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile 2.05 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.4 Hz ,, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), 7.24 (d, J = 1.4 Hz, 1H), 5.35 (s, 2H), 4.91 (brs, 2H), 3.70 (m, 4H), 2.15 (m, 1H), 2.23 (s, 2H), 1.25 (m, 1H), 1.05 (m, 1H) 414

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 165 2- {2-amino-5- [4 (4-pyrrolidin-1 -IIpiperidine-1 carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile 3.9 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.7 Hz „1H), 7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.51 (m, 2H), 7.46 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 5.35 (s, 2H), 4.88 (brs, 2H), 3.95 (m, 4H), 2.55 (m, 4H), 2.30 (m, 1H), 1.95 (m, 2H), 1.76 (m, 4H), 1.52 (m, 2H) 482 I- 166 ο α T jO NH, 2- [2-amino-5- [4 (4-methylpiperazine-1carbonyl) -phenyl] pyridin-3yloxymethyl} benzonitrile 3.2 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz „ 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.51 (m, 2H), 7.48 (m, 2H), 7.24 ( d, J = 1.4 Hz, 1H), 5.35 (s, 2H), 5.01 (brs, 2H), 3.65 (m, 4H), 2.45 (m, 4H), 2.36 (s, 3H) 428 I- 167 o _T O ' ^r T CN rV ^oJ r ^N NH, 2- {5- [4- (4-acetylpiperazine-1carbonyl) -phenyl] -2amino-pyridin-3yloxymethyl} benzonitrile 5.7 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.7 Hz „ 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.54 (m, 2H), 7.50 (m, 2H), 7.26 (d, J = 1.4 Hz, 1H), 5.36 (s, 2H), 5.27 (brs, 2H), 3.65 (m, 8H), 2.14 (s, 3H) 456 I- 168 “Air CN íj ^ o I ^{> N} NH, 4- [6-amino-5- (2-cyano-benciloxy) pyridin-3-yl] -N- (1 methyl-piperidin-4yl) -benzamide 10.8 See example (300 MHz, CDCb) δ 7.99 (d, J = 1.8 Hz „1H), 7.82 (d, J = 8.3 Hz, 2H), 7.74 (m, 1H), 7, 66 (m, 2H), 7.55 (m, 3H), 7.25 (d, J = 1.8 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5, 35 (s, 2H), 4.88 (brs, 2H), 4.05 (m, 1H), 2.96 (m, 1H), 2.46 (s, 3H), 2.40 (m, 1H ), 2.05 (m, 1H), 1.79 (m, 1H), 1.65 (m, 2H), 0.95 (m, 2H) 442

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 169 Y-o CN Α ^ ° Λ ^ ν Λκ, 4- [6-amino-5- (2-cyano-benciloxy) pyridin-3-yl] -N- (2-morpholin-4-yl-ethyl) benzamide 8.6 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz „1H), 7.85 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.4 Hz, 1H), 7.66 (m, 2H), 7.57 (m, 3H), 7.27 (d, J = 1.8 Hz, 1H), 7.06 (m, 1H), 5.36 (s, 2H), 5.14 (brs, 2H), 3.78 (m, 4H), 3 63 (m, 2H), 2.73 (m, 2H), 2.63 (m, 4H) 458 I- 170 CN 4- [6-amino-5- (2cyano- benciloxy) pyridin-3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 17.3 See example (300 MHz, CDCb) δ 8.01 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (m, 1H), 7.56 (d, J = 8.4Hz, 2H), 7.45 (m, 3H), 7.27 (d, J = 1.8 Hz , 1H), 5.36 (s, 2H), 4.89 (brs, 2H), 3.74 (m, 4H), 3.60 (m, 2H), 2.57 (m, 6H), 1 82 (m, 2H) 472 I- 171 CN Í «| 4- [6-amino5- (2,4-dichlorobenciloxy) -pyridin3-yl] -benzoic acid See example (400 MHz, DMSO- de) δ 5.35 (s, 2H, CH ₂ ), 5.90 (brs, 2H, NH ₂ ), 7.30- 8.00 (multiples, 9H, Aromatic) 389 I- 172 O λΧ {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 0.61 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.7 Hz, 1 H), 7.47 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8, 3 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 5.21 (s, 2H), 4.85 (brs, 2H), 4.42 (m, 1H), 3, 50 (m, 2H), 2.84 (m, 4H), 2.2- 1.5 (m, 10H) 527

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 173 P NH. {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 0.66 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.7 Hz, 1H), 7.47 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 5.21 (s, 2H), 4.85 (brs, 2H), 4.42 (m, 1H), 3, 50 (m, 2H), 2.84 (m, 4H), 2.2- 1.5 (m, 10H) 527 I- 174 {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 0.8 See example (300 MHz, CDCb) δ 7.95 (s, 1H), 7.50 (m, 6H), 7.30 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H), 7.20 (s, 1H), 5.21 (s, 2H), 5.07 (brs, 2H), 3.90 (m, 1H), 3.62 (m, 2H), 3.45 (m, 1H), 2.85 (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 1.89 (m, 2H) 486 I- 175 Γ * Ί ^ ° '* Ι * ^Ν NH, {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 1.2 See example 458 I- 176 —O 0 fS ^ ⁰ T ^N αΛ / nh, {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.85 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 3.5 Hz, 1 H), 7.50 (m, 5H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.18 (d, J = 1.8 Hz , 1H), 5.22 (s, 2H), 4.83 (brs, 2H), 4.23 (m, 2H), 2.78 (m, 2H), 1.95 (m, 2H), 1 .76 (m, 3H), 1.25 (m, 4H), 0.85 (m, 4H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 177 the cr ô f X1 Xj ⁰ k {4- [6-amino-5 (2,4-dichlorobenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl) -methanone 0.79 See example (300 MHz, CDCb) δ 7.95 (s, 1H), 7.50 (m, 6H), 7.30 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H), 7.20 (s, 1H), 5.21 (s, 2H), 5.07 (brs, 2H), 3.65 (m, 4H), 2, 45 (m, 4H), 2.36 (s, 3H) 473 I- 178 1 (4- {4- [6-amino5- (2,4-dichlorobenciloxy) -pyridin- 3-yl] -benzoyl} piperazin-1 -II) ethanone 1.67 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.8 Hz, 1H), 7.50 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 5.22 (s, 2H), 4.87 (brs, 2H), 3.64 (m, 4H), 3.53 (m, 4H), 2.14 (s, 3H) 501 I- 179 ò * X. JL «X _α Α>« Η, 4- [6-amino-5- (2,4dichloro-benciloxy) pyridin-3-yl] -N- (1 methyl-piperidin-4yl) -benzamide 1.12 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.46 (m, 2H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1 H), 7.18 (d, J = 1.8 Hz , 1H), 6.09 (br d, 1H), 5.22 (s, 2H), 4.83 (br s, 2H), 4.05 (m, 1H), 3.06 (m, 1H) , 2.46 (s, 3H), 2.32 (m, 1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.26 (m, 2H), 0.88 ( m, 2H) 486 I- 180 _α Χυ ° Ih, 4- [6-amino-5- (2,4dichloro-benciloxy) pyridin-3-yl] -N- (2morpholin-4-yl-ethyl) benzamide 3.8 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.46 (m, 2H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.90 (brt, 1H), 5.22 (s, 2H), 4.91 (brs, 2H), 3.75 (m, 4H), 3.59 (m, 2H), 2.65 (m, 2H), 2.55 (m, 4H) 502

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 181 cr '^ X *' ^{0 IIH} ' 4- [6-amino-5- (2,4dichloro-benciloxy) pyridin-3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 2 See example (300 MHz, CDCb) δ 7.99 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.71 (m, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.47 (m, 2H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H), 5.23 (s, 2H), 4.91 (brs, 2H), 3.75 (m, 4H), 3.59 (m, 2H), 2.60 (m, 6H), 1.83 (m, 2H) 516 I- 182 O ^ OH * f ^F > rS NH, 4- [6-amino5- (2-trifluoromethylbenciloxy) -pyridin3-yl] -benzoic acid See example (400 MHz, DMSO- de) δ 5.35 (s, 2H, CH2), 5.95 (brs, 2H, NH2), 7.40- 8.00 (multiples, 10H, aromatic 388 (M +) I- 183 0 (5 ~ ° · χ {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.75 See example Ή NMR (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7 , 7 Hz, 1H), 7.53 (m, 6H), 7.15 (d, J = 1.7 Hz, 1H), 5.35 (s, 2H), 4.82 (brs, 2H), 4.42 (m, 1H), 3.50 (m, 2H), 2.65 (m, 4H), 2.21.5 (m, 10H) 525 I- 184 ê 0 X JlL Γύ ' ⁰ t ΊΑ NH, {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone > 20 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.7 Hz 1H), 7.53 (m, 6H), 7.15 (d, J = 1.7 Hz, 1H), 5.36 (s, 2H), 4.82 (brs, 2H), 4.42 (m, 1H), 3.50 (m, 2H), 2.65 (m, 4H), 2.2-1.5 (m, 10H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 185 0 irV ° V {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 1.39 See example (300 MHz, CDCb) δ 7.97 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 7, 7 Hz, 1H), 7.51 (m, 6H), 7.16 (d, J = 2.1 Hz, 1H), 5.35 (s, 2H), 4.88 (brs, 2H), 3 , 89 (m, 1H), 3.65 (m, 2H), 3.45 (m, 1H), 2.75 (m, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 2.11 (m, 1H), 1.89 (m, 1H), 485 I- 186 0 rW? MH, [(3S) -3-aminopyrrolidin-1-yl] - {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} methanone 0.79 See example (300 MHz, CDCb) δ 7.93 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.55 (m, 3H), 7.45 (m, 3H), 7.15 (d, J = 1.4 Hz, 1H), 5.35 (s, 2H), 5.01 (br s, 2H), 3.65 (m, 4H), 2.03 (m, 3H), 1.75 (m, 1H), 0.85 (m, 1H) 457 I- 187 _χ σ ° ó {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 1.01 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.66 (m, 1H), 7, 60 (m, 1H), 7.47 (m, 5H), 7.14 (d, J = 1.8 Hz, 1H), 5.35 (s, 2H), 4.81 (brs, 2H), 4.60 (m, 1H), 3.74 (m, 1H), 2.96 (m, 2H), 2.65 (m, 2H), 2.22 (m, 1H), 1.85 (m , 2H), 1.55 (m, 4H), 1.25 (m, 2H), 0.95 (m, 2H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 188 O {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl) -methanone 1.64 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H) , 7.48 (m, 5H), 7.14 (d, J = 1.8 Hz, 1H), 5.35 (s, 2H), 4.89 (brs, 2H), 3.80 (m, 2H), 3.51 (m, 2H), 2.40 (m, 4H), 2.32 (s, 3H) 471 I- 189 THE 1- (4- {4- [6-amino5- (2-trifluoromethylbenciloxy) -pyridin3-yl] -benzoyl} piperazin-1 -II) ethanone 6.7 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H) , 7.48 (m, 5H), 7.14 (d, J = 1.8 Hz, 1H), 5.36 (s, 2H), 4.87 (brs, 2H), 3.64 (m, 4H), 3.53 (m, 4H), 2.14 (s, 3H) 499 I- 190 XH (J Μ NH, {4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-yl] -N- (1-methylpiperidin-4-yl) benzamide 3.8 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.60 (m, 1H), 7.52 ( m, 3H), 7.14 (d, J = 1.8 Hz, 1H), 5.98 (m, 1H), 5.36 (s, 2H), 4.85 (brs, 2H),), 4.05 (m, 1H), 2.90 (m, 2H), 2.32 (s, 3H), 2.18 (m, 2H), 2.01 (m, 2H), 1.62 (m, 2H) 485

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 191 0 M 4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-ll] -N- (2morpholin-4-yl-ethyl) benzamide 5.2 See example (300 MHz, CDCb) δ 7.98 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.53 (m, 3H), 7.17 (d, J = 1.8 Hz, 1H), 6.83 (m, 1H), 5.36 (s, 2H), 4.89 (brs, 2H), 3.74 (m, 4H), 3.57 (m, 2H), 2.62 (m, 2H), 2.52 (m, 4H) 501 I- 192 ^mh j 4- [6-amino-5- (2trifluoromethylbenciloxy) -pyridin3-ll] -N- (2morpholin-4-yl-ethyl) benzamide 3.8 See example (300 MHz, CDCb) δ 7.98 (d, J 1.8 Hz, 1H), 7.95 (m, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.53 (m, 3H), 7.17 (d, J = 1.8 Hz, 1H), 5.36 (s, 2H), 4.94 (brs, 2H), 3.75 (m, 4H), 3.59 (m, 2H), 2.59 (m, 6H), 1.83 (m, 2H) 515 I- 193 0 n k 4- [6-amino- 5- (4-tert-butylbenciloxy) -pyridin- 3-il] -benzoic See example (400 MHZ, DMSO- de) δ 1.25 (s, 9H, t-butyl), 5.20 (s, 2H, CH ₂ ), 5.95 (brs, 2H, NH ₂ ), 7,358.00 ( multiples, 10H, aromatic 376 (M +) I- 194 O {4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 1.89 See example (300 MHz, CDCb) δ 7.94 (d, J = 1.7 Hz, 1H), 7.49 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.80 (br s, 2H), 4.48 (m, 1H), 3.48 (m, 2H), 2.62 (m, 4H), 2.2-1.5 (m, 10H), 1.34 (s, 9H) 513

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 195 P 3rd HH, {4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 3.27 See example (300 MHz, CDCb) δ 7.94 (d, J = 1.7 Hz, 1H), 7.49 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.80 (br s, 2H), 4.48 (m, 1H), 3.48 (m, 2H), 2.62 (m, 4H), 2.2-1.5 (m, 10H), 1.34 (s, 9H) 513 I- 196 the P ò NH, {4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -phenyl} - [(3R) -2dimethylaminopyrrolidin-1 -II] methanone 4.29 See example (300 MHz, CDCb) δ 7.94 (d, J = 2.1 Hz, 1H), 7.54 (m, 4H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s , 2H), 4.84 (brs, 2H), 3.89 (m, 1H), 3.64 (m, 2H), 3.42 (m, 1H), 2.70 (m, 1H), 2 , 31 (s, 3H), 2.22 (s, 3H), 2.05 (m, 1H), 1.89 (m, 1H), 1.34 (s, 9H) 473 I- 197 £ T A ΐίΎΆ ^Ν ^ A ^ NHj {4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl] -methanone 3.8 See example (300 MHz, CDCb) δ 7.93 (d, J = 1.7 Hz, 1H), 7.48 (m, 4H), 7.41 (m, 4H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.85 (brs, 2H), 3.80 (m, 2H), 3.52 (m, 2H), 2.41 (m, 4H), 2.33 (s, 3H), 1.34 (s 9H) 459 I- 198 rA 2nd -A ^ «Hj 1- (4- {4- [6-amino5- (4-tert-butylbenciloxy) -pyridin3-yl] -benzoyl} piperazin-1 -II) ethanone 3 See example (300 MHz, CDCb) δ 7.94 (d, J = 1.8 Hz, 1H), 7.50 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.90 (br s, 2H), 3.64 (m, 4H), 3.53 (m, 4H), 2.14 (s, 3H), 1.34 (s, 9H) 487

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 199 M-0 ô [γνγ 4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -N- (1-methylpiperidin-4-yl) benzamide 2.92 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 6.05 (m, 1H), 5.11 (s, 2H), 4.80 (brs, 2H), 4.01 (m, 1H), 2.84 (m, 2H), 2.33 (s, 3H) 2.20 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H), 1.34 (s, 9H) 487 I- 200 n 4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -N- (2morpholin-4-yl-ethyl) benzamide 6.88 See example (300 MHz, CDCb) δ 7.95 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 6.91 (t, J = 4.6 Hz, 1H), 5.10 (s, 2H), 4.90 (brs, 2H), 3.74 (m, 4H), 3.57 ( m, 2H), 2.62 (m, 2H), 2.51 (m, 4H), 1.34 (s, 9H) 489 I- 201 γΌ 4- [6-amino-5- (4tert-butylbenciloxy) -pyridin3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 6.3 See example (300 MHz, CDCb) δ 8.01 (t, J = 4.5 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 1.8 Hz, 1H), 5.12 (s, 2H), 4.89 (brs, 2H), 3.74 (m, 4H), 3.59 ( m, 2H), 2.56 (m, 6H), 1.82 (m, 2H), 1.34 (s, 9H) 503

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 202 O ^ OH 0 Λ-οώ í | 1 T 4- [6-Amino- acid (2-chloro-4-flourobenciloxy) -pyridin3-yl] -benzoic See example (400 MHz, CDCb) δ 5.25 (s, 2H, CH2), 5.80 (brs, 2H, NH ₂ ), 7.20 - 8.00 (multiples, 9H, aromatics) 374 1- 203 £ o _f A> nh, {4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 1.48 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.7 Hz, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.05 (m, 1H), 5.21 (s, 2H), 4.80 (br s, 2H), 4.45 (m, 1H), 3.52 (m, 2H), 2.76 (m, 4H), 2.2-1.5 (m, 10H) 509 1- 204 _z £> ₀ b I / Xi {4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II] methanone 2.5 See example (300 MHz, CDCI3) δ 7.97 (d, J = 1.7 Hz, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.05 (m, 1H), 5.21 (s, 2H), 4.80 (br s, 2H), 4.45 (m, 1H), 3.52 (m, 2H), 2.76 (m, 4H), 2.2-1.5 (m, 10H) 509 1- 205 Q {4- [6-amino-5- (2chloro-4-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 6.1 See example (300 MHz, CDCb) δ 7.97 (s, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.95 (brs, 2H), 3.90 (m, 1H), 3.61 (m, 2H), 3.33 (m, 1H), 2.75 (m, 1H), 2.32 (s , 3H), 2.23 (s, 3H), 2.10 (m, 1H), 1.89 (m, 1H) 469 1- 206 P {4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 1.83 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.8 Hz, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.84 (br s, 2H), 3.84 (m, 4H), 2.15 (m, 1H), 1.76 (m, 2H), 1.56 (m, 2H) 441

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 207 ô íVV NH, {4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -phenyl} - (4-3methyl-piperazin-1yl] -methanone 5 See example (300 MHz, CDCb) δ 7.96 (s, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H ), 4.89 (brs, 2H) 3.80 (m, 2H), 3.65 (m, 2H), 2.43 (m 4H), 2.33 (s, 3H) 456 1- 208 1- (4- {4- [6-amino5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -benzoyl} piperazin-1 -II) ethanone 5.3 See example (300 MHz, CDCb) δ 7.96 (s, 1H), 7.52 (m, 6H), 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.90 (brs, 2H), 3.67 (m, 4H), 3.53 (m, 4H), 2.22 (s, 3H) 483 1- 209 Μ — O nh, 4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -N- (2morpholin-4-yl-ethyl) benzamide 11 See example (300 MHz, CDCb) δ 7.99 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 6.0 Hz, 8.5 Hz, 1H), 7.20 (m, 2H), 7.04 (m, 1H), 6.82 (m, 1H), 5.22 (s, 2H) , 4.85 (br s, 2H), 3.74 (m, 4H), 3.58 (m, 2H), 2.63 (m, 2H), 2.53 (m, 4H) 485 1- 210 f A ΑλΑ> _F A> ™. 4- [6-amino-5- (2-chloro-4-fluorbenciloxy) -pyridin3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 5.8 See example (300 MHz, CDCb) δ 8.06 (m, 1 H), 7.00 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 6.0 Hz, 8.5 Hz, 1H), 7.20 (m, 2H), 7.04 ( m, IH), 5.22 (s, 2H), 4.85 (br s, 2H), 3.75 (m, 4H), 3.60 (m, 2H), 2.55 (m, 6H), 1.83 (m, 2H) 499 I- 211 O ^ -OH 0 . Ϊ JL1 Yy ° i nh. 4- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] benzoic acid 0.35 See example (300 MHz, DMSO- de) δ 5.21 (s, 2H), 5.71 (s, 2H), 7.31-7.46 (m, 1H), 7.5-7.62 (m, 4H), 7.91-7.94 (m, 3H),

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 212 kA _F Ή {4- [6-amino-5- (2-chloro-3,6-difluorbenciloxy) -pyridin- 3-yl] -phenyl} - (4methyl-piperazin-1ethyl) -methanone 0.063 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 1.6 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 5.29 (s, 2H), 4, 81 (brs, 2H), 3.79 (m, 2H), 3.54 (m, 2H), 3.44 (m, 4H), 2.33 (s, 3H) 473 I- 213 {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.049 See example (300 MHz, CDCb) δ 7.97 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 1.6 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 5.29 (s, 2H), 4, 79 (brs, 2H), 4.60 (m, 1H), 3.85 (m, 1H), 3.02 (m, 2H), 2.65 (m, 4H), 2.35 (m, 1H ), 2.05 (m, 4H), 1.65 (m, 4H), 527 I- 214 F ^ X-σώ UC / X {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - (4 amino- piperidin-1yl) -methanone 0.1 See example (400 MHz, DMSO- de) δ 7.92 (s, 1H), 7.66 (m, 4H), 7.46 (m, 4H), 5.89 (s, 2H), 5.39 (s, 2H), 4.19 (m, 1H), 3.50 (m, 2H) , 2.54 (m, 5H), 1.95 (m, 2H), 1.83 (m, 3H), 1.64 (m, 4H) MS (ES +) m / z 543 (MH +). MS m / z 473 [M + 1] I- 215 ° 5s ^^ - SzXs ^F 'íV ⁰ ' V ^N MH, {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - (3,5-dimethyl-piperazin1-yl) -methanone 0.1 See example (400 MHz, DMSO- de) δ 7.98 (s, 1H), 7.58 (d, 2H), 7.41 (d, 2H), 7.31 (s, 1H), 7.19 (m , 1H), 7.06 (m, 1H), 5.31 (s, 2H), 4.81 (m, 2H), 4.68 (m, 1H), 3.59 (m, 1H), 2 , 89 (m, 2H), 2.69 (m, 1H), 2.40 (m, 1H), 1.74 (m, 1H) 1.18 (d, 6H) 487

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 216 ? oJO . I Λ YY '' ^ NHj {4- [6-amino-5- (2-chloro-3,6-difluorbenciloxy) -pyridin3-yl] -phenyl} - [(2H) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.1 See example (400 MHz, DMSO- de) δ 7.95 (d, 1H), 7.69 (d, 2H), 7.58 (m, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 5.81 (s, 2H), 5.29 (s, 2H), 4.35 (m, 1H), 3.5 (d, 2H) , 2.87 (d, 2H), 2.71 (d, 2H), 1.7-2.0 (m, 10H) 527 I- 217 \ rf Ο ^, Ν ^ / 0 çUXp {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 0.12 See example (400 MHz, DMSO- de) δ 7.97 (s, 1H), 7.60 (m, 4H), 7.32 (s, 1H), 7.18 (m, 1H), 7.04 (m 1H), 5.31 (s, 2H), 4.78 (m, 2H), 3.90 (m, 1H), 3.68 (m, 2H), 3.41 (m, 1H), 2, 78 (m, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 2.04 (m, 1H), 1.84 (m, 1H) 487 I- 218 NH. O UÇ k {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - [(3R) -3amino-pyrrolidin-1yl] -methanone 0.053 See example (400 MHz, DMSO- de) δ 7.84 (s, 1H), 7.62 (m, 5H), 7.35 (m, 1H), 7.20 (m, 1H), 5.38 (s , 2H), 3.78 (m, 3H), 3.55 (m, 1H), 3.41 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H) 459 I- 219 the ^ρ γγνγ '' YA. NH, {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 0.095 See example (400 MHz, DMSO- de) δ 7.84 (s, 1H), 7.62 (m, 5H), 7.35 (m, 1H), 7.20 (m, 1H), 5.38 (s , 2H), 3.78 (m, 3H), 3.55 (m, 1H), 3.41 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H) 459

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 220 ^F 'óç °' V 4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -N- (1-methylpiperidin-4-yl) benzamide 0.11 See example (400 MHz, DMSO- de) δ 7.97 (s, 1H), 7.80 (d, 2H), 7.58 (d, 2H), 7.36 (s, 1H), 7.18 (m , 1H), 7.04 (m, 1H), 6.01 (d, 1H), 5.28 (s, 2H), 4.78 (s, 2H), 3.98 (m, 1H), 2.85 (m, 2H), 2.31 (s, 3H), 2.18 (t, 2H), 2.10 (m, 2H), 1.65 (m, 2H) 487 1- 221 O -ÂnV nh, {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -N- (1-methylapiperidin-4-yl) benzamide 0.18 See example (400 MHz, DMSO- de) δ 7.98 (s, 1H), 7.89 (d, 2H), 7.56 (d, 2H), 7.45 (m, 1H), 7.31 (s , 1H), 7.17 (m, 1H), 7.01 (m, 1H), 5.28 (s, 2H), 4.85 (s, 2H), 3.65 (m, 2H), 2 .89 (t, 2H), 2.76 (m, 4H), 1.89 (m, 4H) 487 I- 222 0 NH, {4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -N- (3pyrrolidin-1 -IIpropyl) - benzamide 0.19 See example (400 MHz, DMSO- de) δ 8.72 (m, 1H), 7.95 (m, 3H), 7.57 (d, 2H), 7.35 (s, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 5.31 (s, 2H), 4.79 (s, 2H), 3.68 (m, 2H), 2.89 (m, 6H), 1.97 (m, 6H) 501 I- 223 UA _f nh. 4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -N- (2morpholin-4-yl-ethyl) benzamide 0.165 See example (400 MHz, DMSO- de) δ 7.97 (s, 1H), 7.82 (d, 2H), 7.62 (d, 2H), 7.36 (s, 1H), 7.18 (m , 1H), 7.05 (m, 1H), 6.81 (m, 1H), 5.28 (s, 2H), 4.79 (s, 2H), 3.78 (m, 4H), 3 .58 (m, 2H), 2.63 (t, 2H), 2.51 (m, 4H) 503

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 224 4- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -N- (3morpholin-4-ylpropyl) - benzamide 0.28 See example (400 MHz, DMSO- de) δ 8.04 (m, 1H), 7.96 (s, 1H), 7.89 (d, 2H), 7.58 (d, 2H), 7.38 (s , 1H), 7.18 (m, 1H), 7.06 (m, 1H), 7.29 (s, 2H), 4.81 (s, 2H), 3.76 (m, 4H), 3.61 (m, 2H), 2.59 (t, 2H), 2.54 (m, 4H), 1.79 (m, 2H) 517 1- 225 0 í ¹ ifS ΥΎ IL NH flacid 3- [6-amino ^c S ^l - (2-chloro-3,6difluoro-benciloxy) pyridin-3- II] benzoic 3.7 / 0.6 See example (300 MHz, CDCb) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.60 (m, 2H), 7.55 (s, 1H), 7.40 (m, 2H), 5.75 ( s, 2H), 5.31 (brs, 2H) 391 1- 226 o OkX W ^ A _f NH2 3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- yl] -phenyl} - (4methyl-piperazin-1yl) -methanone 0.068 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 1.1 Hz, 6.8 Hz, 1H), 7.46 (m, 1H), 7, 35 (m, 3H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.81 (brs, 2H), 3, 83 (m, 2H), 3.50 (m, 2H), 2.49 (m, 2H), 2.39 (m, 2H), 2.33 (s, 3H) 473 1- 227 ΧθΌ '' άζΧ {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.05 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.34 (m, 3H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4 , 77 (brs, 2H), 4.60 (m, 1H), 3.80 (m, 1H), 3.02 (m, 2H), 2.60 (m, 2H), 2.30 (m, 1H), 1.95 (m, 2H), 1.85 (m, 4H), 1.65 (m, 4H) 527

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 228 {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- yl] -phenyl} - (4 amino-piperidin-1- II) -methanone 0.23 See example (300 MHz, CD-3 OD) δ 8.01 (s, 1H), 7.89 (s, 1H), 7.75 (m, 2H), 7.59 (s, 1H), 7.48 (t, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 5.38 (s, 2H), 4.0l (m, 1H), 3.09 (m, 2H), 2.68 (t, 2H), 1.97 (m, 2H), 1.58 (m, 2H) 473 1- 229 ç / çc 'Xj-o-Ç' NH, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} - (3,5-dimethyl-piperazin1-yl) -methanone 0.066 / 0.18 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.56 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.36 (m, 3H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.82 (brs, 2H), 4.68 (m, 1H), 3.65 (m, 1H), 3.90 (m, 2H), 2.70 (m, 1H), 2.40 (m, 1H), 1.97 (m, 1H), 1.15 (d, 3H), 0.99 (d, 3H) 487 1- 230 Í r-O ÇTÓ XpAf kA, <· Η, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- il] -phenyl} - [(2S) - 2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl] -methanone 0.19 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 1.7 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.78 (br s, 2H), 4.42 (m, 1H), 3.45 (m, 2H), 2.68 (m, 4H), 2.2-1.5 (m, 10H) 527 1- 231 o \> < Άρ ° τ kA, · «, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} - [(3S) 3-dimethylaminopyrrolidin-1 -II] methanone 0.128 See example (300 MHz, CDCb) δ 7.96 (s, 1H), 7.68 (d, J = 7.4 Hz, 1H), 759 (m, 1H), 7.44 (m, 2H), 7, 36 (s, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.80 (brs, 2H), 3.90 (m, 1H), 3.61 (m, 2H), 3.41 (m, 1H), 2.77 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 2.10 (m, 1H), 1.82 (m, 1H) 487

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 232 {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- il] -phenyl} - [(3R) - 3-amino-pyrrolidin- 1-il] -methanone 0.12 See example (300 MHz, CD3OD) δ 7.86 (m, 1H), 7.75 (m, 2H), 7.58 (m, 3H), 7.38 (m, 1H), 7.22 (m, 1H ), 5.38 (s, 2H), 4.00- 3.56 (m, 5H), 2.40 (m, 1H), 2.12 (m, 1H) 459 1- 233 fJA ώ Yy o] nh, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- il] -phenyl} - [(3S) - amino-pyrrolidin-1yl] -methanone 0.12 See example (300 MHz, CD3OD) δ 7.86 (s, 1H), 7.75 (m, 2H), 7.58 (m, 3H), 7.38 (m, 1H), 7.22 (m, 1H ), 5.38 (s, 2H), 4.00- 3.56 (m, 5H), 2.40 (m, 1H), 2.12 (m, 1H), 459 1- 234 (ΓΤ X, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -phenyl} -N- (1methyl-piperidin-4yl) -benzamide 0.23 See example (300 MHz, CDCb) δ 7.96 (d, J = 1.7 Hz, 1H), 7.94 (s, 1H), 7.64 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 6.25 (m, 1H), 5.27 (s, 2H), 4.81 (brs, 2H), 3.99 (m, 1H), 2.84 (m, 2H), 2.30 (s, 3H), 2.16 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H) 487 1- 235 CT ^ tT ^^ kÀf NH, {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} -N- (2pyrrolidin-1-yl-ethyl) benzamide 0.26 See example (300 MHz, CDCb) δ 8.02 (s, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7, 64 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.20 (m, 2H), 7.06 (m, 1H), 5.27 (s, 2H), 4.83 (brs, 2H), 3.61 (m, 2H), 2.77 (m, 2H), 2.62 (m, 4H), 1.81 (m, 4H) 487

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 236 {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} -N- (3pyrrolidin-1 -IIpropyl) -benzamide 0.28 See example (300 MHz, CDCb) δ 8.78 (m, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.45 (t , J = 7.7 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 5.29 (s , 2H), 4.77 (brs, 2H), 3.61 (m, 2H), 2.77 (m, 2H), 2.66 (m, 4H), 1.87 (m, 2H), 1 .80 (m, 4H) 501 1- 237 {3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -phenyl} -N- (2morpholin-4-yl-ethyl) benzamide 0.35 See example (300 MHz, CDCb) δ 7.89 (t, J = 1.5 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.66 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 2H), 5.27 (s, 2H), 4.85 (brs, 2H), 3.72 (m, 4H), 3.59 (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H) 503 1- 238 3- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3-yl] -N- (3morpholin-4-ylpropyl) -benzamide 0.35 See example (300 MHz, CDCb) δ 8.02 (m, 2H), 7.97 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7, 65 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.19 ( m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.81 (brs, 2H), 3.66 (m, 4H), 3.59 (m, 2H), 2, 55 (m, 2H), 2.49 (m, 4H), 1.81 (m, 2H) 517

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 239 N- [2- (4-acetylpiperazin-1 -II) ethyl] -3- [6-amino-5 (2-chloro-3,6-difluoro-benciloxy) pyridin-3- II] - benzamide 0.1 See example (300 MHz, CDCb) δ 8.00 (s, 1H), 7.86 (s, 1H), 7.67 (dd, 2H), 7.56 (t, 1H), 7.48 (s, 1H), 7.21 (m, 1H), 7.08 (m, 1H), 6.02 (brs, 2H), 5.39 (s, 2H), 3.75 (m, 4H), 3.60 (m, 2H), 2.79 (m, 2H) , 2.60 (m, 4H), 2.11 (s, 3H) 544 1- 240 ° ^ 'N T JQ F 3- (2-chloro-3,6difluoro-bencilóxi) 5- [4- (1,1-dioxo1 À ⁶ -isotizolidin-2il) -phenyl] -pyridin-2ylamine 0.1 See example (400 MHz, DMSO- de) δ 7.88 (s, 1H), 7.62 (d, 2H), 7.56 (m, 1H), 7.51 (s, 1H), 7.40 (m, 1H), 7.23 (d, 2H), 5.70 (s, 2H), 5.28 (s, 2H), 3.78 (t, 2H), 3.49 (t, 2H), 2.41 (t, 2H) 466 1- 241 0 NH ^ν NH, 3- (2,6-dichlorobenciloxy) -5- [4 (1,1-dioxo-1 λ ^β isotizolidin-2-yl) phenyl] -pyridin-2ylamine 0.067 See example 464 I- 242 ò Λ fV ° T Xí ^ CF ₃ ^nh * 5- (4- (1,1-dioxo- 1 À ⁶ -isotizolidin-2yl) -phenyl] -3- (2-fluoro-6-trifluoromethylbenciloxy) -pyridin-2-ylamine 0.14 See example 482 I- 243 2-diethylamino acid ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.043 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 4.70 (brs, 2H), 3.22 (t, J = 6.1 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.65 (q, J = 7.1 Hz, 4H), 1.10 (t, J = 7.1 Hz, 6H) 525

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 244 λαΦ L _j A _to NH, F 2cyclopropylamino acid ethanesulfonic {4- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 0.081 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 4.75 (brs, 2H), 3.25 (s, 4H), 2.17 (m, 1H), 0.9 (m, 1H), 0.50 (m, 2H), 0.40 (m, 2H) 509 1- 245 s O ίητ τ «Η. 2-pyrrolidin-1 -II ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 0.082 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 4.72 (brs, 2H), 3.27 (m, 2H), 3.06 (m, 2H), 2.59 (m, 4H), 1.86 (m, 4H) 523 1- 246 ff ya. / · <- · ί ^! 2- (4-hydroxypiperidin-1 -II) ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.135 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.32 (m, 2H), 7.24 (m, 2H), 7.20 (m, 1H), 7.07 ( m, 1H), 5.28 (s, 2H), 4.74 (brs, 2H), 3.81 (m, 1H), 3.31 (t, 2H), 2.98 (t, 2H), 2.85 (m, 2H), 2.32 (m, 2H), 1.98 (m , 2H), 1.68 (m, 3H) 553 1- 247 xpo Αχθ-Φ 2-morpholin-4-yl ethanesulfonic acid {4- [6-amino- 5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 0.31 See example (300 MHz, DMSO- de) δ 9.80 (brs, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.59 (m, 3H), 7.52 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 5.72 (brs, 2H), 5.28 (s, 2H), 3.49 (m, 4H), 3.28 (t, 2H), 2.69 (t, 2H), 2.31 (m, 4H) 539

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 248 ¹ 0 jQ NH _to F 2-piperidin-1 -II ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 0.114 See example (300 MHz, CDCb) δ 7.93 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.30 (m, 2H), 7.24 (m, 2H), 7.20 (m, 1H), 7.07 ( m, 1H), 5.28 (s, 2H), 4.70 (brs, 2H), 3.25 (t, 2H), 2.92 (t, 2H), 2.52 (m, 4H), 1.85 (m, 4H), 1.63 (m, 2H) 537 1- 249 í? ^H fYYY TX JU M-α 2-dimethylamine-ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.098 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.30 (m, 2H), 7.24 (m, 2H), 7.20 (m, 1H), 7.07 ( m, 1H), 5.28 (s, 2H), 4.71 (brs, 2H), 3.20 (t, 2H), 2.88 (t, 2H), 2.32 (s, 6H) 497 1- 250 Ϊ ^ ΌγΟ φττ 2- (4-acetylpiperazin-1-yl) ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.42 See example (300 MHz, CDCb) δ 7.92 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.30 (m, 2H), 7, 24 (m, 1H) 7.20 (m, 1H), 7.07 (m, 2H), 5.28 (s, 2H), 4.80 (brs, 2H), 3.65 (m, 2H) , 3.48 (m, 2H), 3.32 (t, 2H), 2.94 (t, 2H), 2.50 (m, 2H) 2.46 (m, 2H), 2.10 (s, 3H) 580 1- 251 2 (cyclopropylmethylamino) ethanesulfonic acid {4 [6-amino-5- (2chloro-3,6-difluorborboxy) -pyridin3-yl] -phenyl} -amide 0.075 See example (300 MHz, CDCb) δ 7.94 (s, 1H), 7.48 (m, 2H), 7.31 (m, 3H), 7.21 (m, 1H), 7.18 (m, 1H ), 5.28 (s, 2H), 4.75 (s, 2H), 3.23 (m, 4H), 2.58 (m, 2H), 1.00 (m, 1H), 0.56 (m, 2H), 0.18 (m, 2H) 523

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 252 2 - [(3R) -3-hydroxypyrrolidin-1-yl] ethanesulfonic acid {4- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.125 See example (300 MHz, CDCb) δ 7.92 (s, 1H), 7.43 (m, 2H), 7.31 (m, 3H), 7.19 (m, 1H), 7.05 (m, 1H ), 5.28 (s, 2H), 4.75 (s, 2H), 4.45 (m, 1H), 3.29 (m, 2H), 3.10 (m, 3H), 2.88 (m, 1H), 2.61 (m, 1H), 2.30 (m, 2H), 1.89 (m, 2H) 539 1- 253 í çCX 2 - [(2S) -2hydroxymethyl-pyrrolidin-1 -II] - ethanesulfonic acid {4 [6-amino-5- (2-chloro-3,6-difluorbyloxy) -pyridin3-yl] -phenyl} -amide and 0.097 See example (300 MHz, CDCb) δ 7.89 (s, 1H), 7.45 (m, 2H), 7.30 (m, 3H), 7.21 (m, 1H), 7.08 (m, 1H ), 5.31 (s, 2H), 4.78 (s, 2H), 3.55 (m, 2H), 3.36 (t, 1H), 3.11 (m, 2H), 2.69 (m, 2H), 2.21 (m, 1H), 1.89 (m, 6H) 553 1- 254 ihx X φτχ 2- [4- (2-hydroxyacetyl) -piperazin1-yl] - ethanesulfonic acid {4- [6- amino-5- (2-chloro3,6-difluorborboxy) -pyridin- 3- il] -phenyl} -amide 0.18 See example (300 MHz, DMSO- de) δ 9.81 (s, 1H), 7.89 (s, 1H), 7.58 (d, 2H), 7.50 (s, 1H), 7.39 (m , 2H), 7.24 (d, 2H), 5.75 (s, 2H), 5.28 (s, 2H), 4.54 (t, 1H), 4.01 (d, 2H), 3.29 (m, 6H), 2.79 (t, 2H), 2.36 (m, 4H) 596 1- 255 2- (4-acetylpiperazin-1 -II) ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 0.68 See example (300 MHz, CDCb) δ 2.02 (s, 3H), 2.30 (m, 4H), 2.95 (m, 4H), 3.35 (m, 4H), 3.55 (m, 2H ), 5.30 (d, 2H), 5.42 (s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.35 (m, 5H), 8.00 (d, 1H), 10.17 (s, 1H) 580

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 256 2-pyrrolidin-1 -II ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 0.23 See example (300 MHz, CDCb) δ 1.60-1.80 (m, 4H), 2.40-2.55 (m, 4H), 3.02 (t, J = 6.6 Hz, 2H), 3.29 (t, J = 6.6 Hz, 2H), 5.08 (s, 2H), 5.29 (d, J = 1.3 Hz, 2H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.25-7.45 (m, 5H), 7.97 (d, J = 1.7 Hz, 1 H) 524 1- 257 2-morpholin-4-yl ethanesulfonic acid {3- [6-amino- 5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 1.64 See example (300 MHz, CDCb) δ 2.42 (t, J = 4.6 Hz, 4H), 2.90 (t, J = 6.9 Hz, 2H), 3.31 (t, J = 6.9 Hz, 2H), 3.62 (t, J = 4.6 Hz, 4H), 5.24 (s, 2H), 5.30 (d, J = 1.3 Hz, 2H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.30-7.45 (m, 5H), 7.99 (d, J = 1.6 Hz, 1H), 9.38 (s, 1H) 540 1- 258 2-diethylamine-ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 1.67 See example (300 MHz, CDCb) δ 1.00 (t, 6H), 2.52 (q, 4H), 3.02 (t, 2H), 3.25 (t, 2H), 5.19 (s, 2H), 5.29 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.35 (m, 5H), 7.98 (d, 1H) 526 1- 259 ΓχψΆ O % Ap NH, 2-dimethylamine-ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 1.5 See example (300 MHz, CDCb) δ 2.24 (s, 6H), 2.85 (t, 2H), 3.24 (t, 2H), 5.11 (s, 2H), 5.29 (d, 2H ), 7.07 (m, 1H), 7.15 (m, 1H), 7.35 (m, 5H), 7.98 (d, 1H) 498

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 260 ÇrÍ ~ ⁰ 2-piperidin-1 -II ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} amide 1.63 See example (300 MHz, CDCb) δ 1.30 - 1.60 (m, 6H), 2.30 - 2.45 (m, 4H), 2.89 (t, J = 6.7 Hz, 2H), 2.28 (t, J = 6.7 Hz, 2H), 5.13 (s, 2H), 5.29 (d, J = 1.4 Hz, 2H), 6.95-7.05 (m, 1H), 7.15-7.45 (m, 6H), 7.98 (d, J = 1.6 Hz, 1H) 538 1- 261 2 - [(3R) -3hydroxymethylpyrrolidin-1 -II] ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 1.7 See example (300 MHz, CDCb) δ 1.60-1.8 (m, 4H), 2.05-2.15 (m, 1H), 2.55-2.75 (m, 2H), 2.95- 3.15 (m, 2H), 3.25 - 3.55 (m, 3H), 3.82 (dd, J = 3.0, 11.2 Hz, 1H), 4.97 (s, 2H), 5.28 (d, J = 1.6 Hz, 2H), 6.98 - 7.08 (m, 1H), 7.10-7.20 (m, 1H), 7.25-7.45 (m, 5H), 7.98 (d, J = 1.8 Hz, 1H) 554 I- 262 'Óç ¹⁰ 2- (3-hydroxypiperidin-1-yl) ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 1.5 See example (300 MHz, DMSO- de) δ 1.15-1.30 (m, 2H), 1.45-1.55 (m, 2H), 1.90-2.02 (m, 2H), 2.50-2.70 (m, 4H), 4.49 (brs, 1H), 5.28 ( s, 2H), 5.82 (s, 2H), 7.05-7.10 (m, 1H), 7.20- 7.40 (m, 5H), 7.45- 7.60 (m, 1H), 7.83 (d, J = 1.6 Hz, 1H) 554

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 263 2- [4- (2-hydroxyacetyl) piperazin1 -yl] -ethanesulfonic acid {3- [6- amino-5- (2-chloro3,6-difluorborboxy) -pyridin- 3- il] -phenyl} -amide 1.14 See example (300 MHz, CDCb) δ 2.36 (m, 4H), 2.92 (t, 2H), 3.14 (m, 2H), 3.32 (t, 2H), 3.54 (m, 2H), 3.60 (brs, 1H), 4.07 (s, 2H), 5.30 (s, 2H), 5.40 (brs, 2H), 7.06 (m, 1H), 7.24 (m, 2H), 7.34 (m, 2H), 7.44 (m, 2H), 7.99 (d, J = 1.6 Hz, 1H), 9.88 (brs, 1H) 596 1- 264 2 - [(3R) -3-hydroxypyrrolidin-1 -II] ethanesulfonic acid {3- [6-amino5- (2-chloro-3,6difluor-benciloxy) pyridin-3-yl] -phenyl} amide 1,097 See example (300 MHz, CDCb) δ 1.65 (m, 1H), 2.08 (m, 1H), 2.22 (m, 1H), 2.46 (m, 1H), 2.76 (m, 1H ), 2.87 (m, 1H), 3.02 (m, 2H), 3.32 (m, 2H), 4.28 (m, 1H), 5.28 (brs, 2H) 5.29 ( s, 2H), 7.06 (m, 1H), 7.24 (m, 2H), 7.44 (m, 5H), 8.00 (d, J = 1.7 Hz, 1H) 539 1- 265 PT 2 (cyclopropylmethylamino) ethanesulfonic acid {3 [6-amino-5- (2chloro-3,6-difluorborboxy) -pyridin3-yl] -phenyl} -amide 1 See example (300 MHz, CDCb) δ 0.02 (m, 2H), 0.39 (m, 2H), 0.84 (m, 1H), 2.40 (d, 2H), 3.14 (t, 2H), 3.32 (t, 2H), 5.28 (s, 2H), 5.38 (brs, 2H), 7.06 (m, 1H), 7.24 (m, 2H), 7.44 (m, 5H), 8.00 (d, J = 1.7 Hz, 1H) 523 1- 266 ΖγΜ / SziiH 2 (cyclopropylamino) - ethanesulfonic acid {3- [6 amino-5- (2-chloro3,6-difluorbyloxy) -pyridin3-yl] -phenyl} -amide 0.9 See example (300 MHz, CDCb) δ 0.28 (m, 2H), 0.37 (m, 2H), 2.06 (m, 1H), 3.15-3.40 (m, 4H), 5.30 (d, 2H), 5.39 (s, 2H), 7.07 (m, 1H), 7.19 (m, 1H), 7.30 - 7.55 (m, 5H), 8.01 (d, 1H) 509

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 267 Ojl ΙίΥ ^ο Ύ F 3- (2-chloro-3,6difluoro-benciloxy) 5- (2dimethylaminomethylphenyl) -pyridin-2ylamine; composed with trifluoracetic acid See example 404 1- 268 rjr ΦΧ 3- (2-chloro-3,6difluoro-benciloxy) 5- (2-pyrrolidin-1-IIIphenyl) -pyridin-2ylamine; composed with trifluoracetic acid 4 See example (400 MHz, DMSO- de) δ 1.94 (t, 4H), 3.31 (t, 4H), 5.44 (s, 2H), 6.56 (d, 1H), 6.74 (s, 1H), 6.88 (d, 1H), 7.24 (t, 1H), 7.43 (m, 1H), 7.58 (m, 3H), 7.83 (m, 2H) 416 1- 269 ηΛο Ϊ jl Y ^ CI ^NH > F N- {4- [6-amino-5 (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] -phenyl} methanesulfonamide; composed with trifluoroacetic acid See example (400 MHz, DMSO- de) δ 2.99 (s, 3H), 5.35 (s, 2H), 6.72 (brs, 2H), 7.27 (d, 2H), 7.42 (m, 1H), 7.59 (m, 1H), 7.65 (d, 2H), 7.73 (s, 1H), 7.84 (s, 1H), 9.79 (s, 1H) 440 1- 270 5- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] thiophene-2-carbolic acid See example 397 1- 271 ψττ {5- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -tiofen-2-yl} (4-methyl-piperazin1-yl) -methanone See example (300 MHz, CDCb) δ 8.00 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.20 (m, 1H), 7.10 (d, J = 3.8 Hz, 1H), 7.07 (m, 1H), 5.27 (d, J = 1.7 Hz, 2H), 4.82 (brs, 2H), 3.81 (m, 4H), 2.47 (m, 4H), 2.34 (s, 3H) 479

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 272 O ÇCA {5- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin- 3- il] -tiofen-2-il} - [(2H) -2-pyrrolidin- 1 -ylmethyl-pyrrolidin- 1-il] -methanone See example (300 MHz, CDCb) δ 8.02 (d, J = 1.8 Hz, 1H), 7.52 (m, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.21 (m, 1H), 7.14 (d, J = 3.9 Hz, 1H), 7.07 (m, 1H), 5.27 (d, J = 1.5 Hz, 2H), 4.80 (brs, 2H), 4.50 (m, 1H), 3.81 (m, 2H), 2.74 (m, 4H), 2.25 - 1.82 (m, 10H), 533 1- 273 Ç / 8 5- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] thiophene-2-carboxylic acid (1-methyl-piperidin-4yl) -amide See example (300 MHz, CDCb) δ 8.02 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 3.9 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.21 (m, 1H), 7.15 (d, J = 3.9 Hz, 1H), 7.07 (m, 1H), 5.89 (br d, 1H), 5.29 (d, J = 1.5 Hz, 2H), 4.62 (brs, 2H), 4.05 (m, 1H), 3.05 (m, 2H), 2.50 (s, 3H), 2.40 (m, 2H), 1.85 (m, 2H), 1.62 (m, 2H) 493 1- 274 Ph y Y ^ ci ^NH = {5- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -tiophen-2-yl} (3,5-dimethylpiperazin-1 -II) methanone See example (300 MHz, CDCb) δ 8.00 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 7.21 (m, 1H), 7.10 (d, J = 3.8 Hz, 1H), 7.07 (m, 1H), 5.28 (d, J = 1.5 Hz, 2H), 4.82 (brs, 2H), 4.38 (m, 2H), 2.98 (m, 2H), 2.65 (m, 2H), 1.68 (brs, 1H), 1.11 (d, J = 6.2 Hz, 6H) 493

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 275 y-x F 5- [6-amino5- (2-chloro-3,6difluoro-benciloxy) pyridin-3-yl] thiophene-2-carboxylic acid (2pyrrolidin-1-yl-ethyl) amide See example (300 MHz, CDCb) δ 8.00 (d, J = 1.8 Hz, 1H), 7.82 (brm, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7, 29 (d, J = 1.8 Hz, 1H), 7.21 (m, 1H), 7.11 (d, J = 3.9 Hz, 1H), 7.07 (m, 1H), 5.26 (d, J = 1.5 Hz, 2H), 4.81 (brs, 2H), 3.71 (m, 2H), 3.02 (m, 2H), 2.95 (m, 2H), 2 , 01 (m, 4H), 1.97 (m, 2H), 1.11 (d, J = 6.2 Hz, 6H) 493 1- 276 γοο κβ {5- [6-amino-5- (2-chloro-3,6-diflúorbenciloxy) -pyridin3-yl] -tiofen-2-yl} (4-pyrrolidin-1 -IIpiperidin-1 -II) methanone See example (300 MHz, CDCb) δ 6.00 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 7.20 (m, 1H), 7.09 (d, J = 3.8 Hz, 1H), 7.07 (m, 1H), 5.27 (d, J = 1.5 Hz, 2H), 4.80 (brs, 2H), 4.43 (m, 2H), 3.10 (m, 2H), 2.63 (m, 4H), 2.34 (m, 1H), 1.99 (m, 2H), 1.83 (m , 4H), 1.63 (m, 2H), 533 1- 277 ° <^ χ ^0Μ T Λ PC * ^NH - F 4- [6-amino5- (3-fluro-2trifluoromethylbenciloxy) -pyridin3-yl] -benzoic acid See example 407 1- 278 JL ^ h ÇQT F {4- [6-amino-5- (3fluro-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II] methanone See example (300 MHz, CDCb) δ 7.97 (d, J = 1.8 Hz, 1H), 7.61-7.42 (m, 6H), 7.21 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 5.33 (s, 2H), 4.81 (brs, 2H), 4.62 (m, 1H), 3.84 (m, 1H), 2.98 (m, 2H), 2.65 (m, 4H), 2.32 (m, 1H), 1, 97 (m, 2H), 1.84 (m, 4H) 1.60 (m, 2H) 543

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 279 r 4- [6-amino-5- (3fluro-2trifluoromethylbenciloxy) -pyridin3-yl] -N- (1-methylpiperidin-4-yl] benzamide See example (300 MHz, CDCb) δ 7.99 (d, J 1.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.55 (m, 1 H), 7.52 (d, J = 8.3 Hz, 2H>, 7.44 (d, J 7.8 Hz, 1H), 7.22 (1, = 8.7 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 5.99 (br d, 1 R), 5.34 (s, 2H), 4.83 (brs, 2H), 4.04 (m, 1 H), 2.87 (m, 21-1), 2.34 (s, OH), 2.20 (m, 2H), 2.05 (m, 2H), 1.63 (m, 2H) 503 1- 280 Λ 0 children ^ο {4- [6-amino-5- (3fluro-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (3,5dimethyl-piperazin1-yl] -methanone See example (300 MHz, CDCb) δ 7.98 (s, 1 H), 7.617.43 (m, 6H), 7.22 (t, J = 8.7 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H) , 5.33 (s, 2H), 4.82 (brs, 2H), 4.65 (m, 1H), 3.65 (m, 1H), 2.90 (m, 2H), 2.68 ( m, 1H), 2.42 (m, 1H), 1.60 (m, 1H), 1.12 (d, 3H), 1.00 (d, 3H) 503 1- 281 0 No. L Y ^ C *. {4- [6-amino-5- (3fluro-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (3dimethylaminopyrrolidin-1 -II] methanone See example (300 MHz, CDCb) δ 7.98 (d, J = 2.4 Hz, 1H), 7.61-7.43 (m, 6H), 7.21 (t, J = 8.8 Hz, 1H ), 7.14 (d, J = 2.4 Hz, 1H), 5.33 (s, 2H), 4.87 (brs, 2H), 3.89 (m, 1H), 3.65 (m , 2H), 3.42 (m, 1H), 2.70 1.02 (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.14 (m, 1H), 1.82 (m, 1H), 503

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 282 iO -O r {4- [6-amino-5- (3fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - [(2S) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone See example (300 MHz, CDCb) δ 7.98 (d, J = 1.4 Hz, 1H), 7.58-7.43 (m, 6H), 7.20 (t, J = 8.8 Hz, 1H ), 7.13 (d, J = 1.4 Hz, 1H), 5.34 (s, 2H), 4.81 (brs, 2H), 4.46 (m, 1H), 7.50 (m, 2H), 2.77 (m, 4H), 2.30 - 1.50 (m, 10H) 543 1- 283 X ^ '0 F 4- [6-amino-5- (3fluor-2trifluoromethylbenciloxy) -pyridin3-yl] - # NI- (2morpholin-4-yl-ethyl) benzamide See example (300 MHz, CDCb) δ 8.00 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.56 (m, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, 1H), 7.20 (t, J = 8.8 Hz, 1H), 7.13 (d, J = 1.4 Hz, 1H), 6.76 (m, 1H), 5.34 (s, 2H), 4.85 (brs, 2H), 3.74 (m, 4H ), 3.56 (m, 2H), 2.62 (m, 2H), 2.52 (m, 4H) 519 1- 284 O. ^ -nAzA '0 ççn? {4- [6-amino-5- (3fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -phenyl} - (4methyl-piperazin-1yl] -methanone See example (300 MHz, CDCb) δ 7.97 (d, J = 1.8 Hz, 1H), 7.58-7.43 (m, 6H), 7.20 (t, J = 8.8 Hz, 1H ), 7.12 (d, J = 1.8 Hz, 1H), 5.34 (s, 2H), 4.93 (brs, 2H), 3.80 (m, 2H), 3.56 (m , 2H), 2.44 (m, 4H), 2.33 (s, 3H) 489

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 285 N- [2- (4-acetylpiperazin-1-11) ethyl] -4- [6-amino-5 (3-fluor-2trifluoromethylbenciloxy) -pyridin3-yl] -benzamide See example (300 MHz, CDCb) δ 8.00 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.58 (m, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 6.72 (m, 1H), 5.34 ( s, 2H), 4.85 (brs, 2H), 3.65 (m, 2H), 3.60 (m, 2H), 3.50 (m, 2H), 2.65 (m, 2H), 2.51 (m, 4H) , 2.10 (s, 3H) 560 1- 286 O Φ0 £ · F 2-piperidin-1 -II ethanesulfonic acid (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.18 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.26 (d, 2H), 7.20 (d, 2H), 7.06 (m, 3H), 7.59 (s, 1H ), 4.86 (s, 2H), 3.25 (m, 2H), 2.89 (m, 2H), 2.49 (m, 4H), 1.83 (d, 3H), 1.62 (m, 4H), 1.48 (m, 2H) 551 1- 287 2- (4-hydroxypiperidin-1 -II) ethanesulfonic acid (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.14 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.26 (d, 2H), 7.20 (d, 2H), 7.06 (m, 3H), 7.59 (s, 1H ), 4.86 (s, 2H), 3.76 (m, 1H), 3.25 (m, 2H), 2.89 (m, 2H), 2.78 (m, 2H), 2.26 (m, 2H), 1.83 (m, 5H), 1.62 (m, 2H) 567 1- 288 fl 2-dimethylamino acid ethanesulfonic (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.15 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.26 (d, 2H), 7.20 (d, 2H), 7.06 (m, 3H), 7.59 (s, 1H ), 4.86 (s, 2H), 3.21 (m, 2H), 2.88 (m, 2H), 2.30 (s, 6H), 2.26 (m, 2H), 1.82 (d, 3H) 511

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 289 0 2cyclopropylamino acid ethanesulfonic (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.16 See example (300 MHz, CDCb) δ 7.89 (s, 1H), 7.38 (d, 2H), 7.26 (d, 2H), 7.18 (m, 3H), 5.95 (m, 1H), 4.89 (s, 2H), 3.22 (m, 4H), 2.14 (m, 1H), 1.85 (d, 3H), 0.50 (m, 2H), 0.38 (m, 2H) 523 1- 290 Ο ^ χΟΗ Cl 1 NH, 4- {6-amino- 5- [1- (2,6-dichloro- 3-fluro-2-phenyl) ethoxy] -pyridin-3-yl} benzoic See example 422 1- 291 THE (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) [(2H) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl) -methanone 0.063 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.52 (d, 2H), 7.31 (d, 2H), 7.08 (m, 3H), 6.13 (m, 1H ), 4.86 (s, 2H), 4.30 (m, 1H), 3.40 (m, 2H), 2.60 (m, 4H), 1.82 (d, 3H), 1.70 -2.0 (m, 10H) 557 I- 292 vÇW Ά w. (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (1 methyl-piperidin-4yl) -benzamide 0.069 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.78 (d, 2H), 7.35 (d, 2H), 7.31 (m, 3H), 6.16 (tert, 1H), 5.90 (d, 1H), 4.86 (s, 2H), 4.05 (m, 1H), 2.85 (d, 1H), 2.35 (s, 3H), 2.05 (d, 1H), 2.25 (t, 1H), 1.82 (d, 3H), 1.60 (m, 1H), 1.29 (m, 2H), 0.86 (m, 2H) 559 I- 293 çA> ' O (3- {6-amino-5- [1 (2,6-dichloro-3- fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) [(3R) -3-aminopyrrolidin-1 -II)] methanone 0.051 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.51 (s, 1H), 7.38 (m, 3H), 7.30 (m, 1H), 7.15 (m, 1H), 6.97 (s, 1H), 6.15 (m, 1H), 4.94 (s, 2H), 3,453.89 (m, 4H), 3.20 (m, 1H), 2.25 (m, 1H), 2.15 (m, 1H), 1.82 (d, 3H), 1.34 (m, 2H) 489

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 294 Q (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-pyrrolidin-1 -IIpiridin-3-yl) methanone 0.062 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.70 (m, 1 H) 7.45 (m, 1H), 7.30 (s, 2H), 7.08 (t, 1H), 6.92 (d, 2H), 6.13 (m, 1H), 4.86 (s, 2H), 4.30 (t, 1H) , 2.80 (m, 4H), 1.82 (d, 3H), 1.80 (m, 4H), 1.35 (m, 4H), 0.89 (m, 4H) 559 1- 295 (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-methyl-piperazin1-yl) -methanone 0.079 See example (300 MHz, CDCb) δ 7.89 (s, 1H), 7.71 (d, 2H), 7.49 (d, 2H), 7.40 (s, 1H), 7.35 (m, 1H ), 7.08 (m, 1H), 6.17 (m, 1H), 4.98 (s, 2H), 4.28 (t, 2H), 3.68 (m, 4H), 2.38 (m, 2H), 2.31 (s, 3H), 1.88 (d, 3H) 503 1- 296 rXAoV (4- {6-amino-5- [1 (2,6-dichloro-3- fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (3,5-dimethylpiperazi-1 -II) methanone 0.054 See example 1- 297 4 ^ 0 dW kA _cl «<, 2cyclopropylamino acid ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro3-fluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.164 See example (300 MHz, CDCb) δ 7.79 (s, 1H), 7.30 (m, 3H), 7.24 (m, 3H), 7.08 (t, 1H), 6.95 (s, 1H), 6.09 (m, 1H), 4.89 (s, 2H), 3.21 (m, 4H), 2.12 (m, 1H), 1.84 (d, 3H), 0.87 (m , 1H), 0.50 (m, 2H), 0.36 (m, 2H) 539 1- 298 ϊ ò <A _ct 2-dimethylamine-ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro3-fluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.059 See example (300 MHz, CDCb) δ 7.81 (s, 1H), 7.26 (m, 6H), 7.04 (t, 1H), 6.94 (s, 1H), 6.12 (m, 1H ), 4.95 (s, 2H), 3.21 (t, 2H), 2.85 (t, 2H), 2.31 (s, 6H), 1.85 (d, 3H) 527

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 299 Xq- « 2 - [(3R) -3-hydroxypyrrolidin-1-yl)] ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro3-fluor-phenyl) ethoxy] -pyridin-3-yl} phenyl ) -amide 0.062 See example (300 MHz, CDCb) δ 7.84 (d, 1H), 7.30 (m, 5H), 7.10 (t, 1H), 6.89 (s, 1H), 6.10 (tert, 1H ), 4.86 (s, 2H), 4.40 (s, 1H), 3.21 (m, 2H), 2.88 (m, 3H), 2.67 (d, 1H), 2.46 (m , 1H), 2.20 (m, 2H), 2.05 (s, 1H), 1.85 (d, 3H), 1.25 (s, 1H) 570 1- 300 pv N- [2- (4-acetyl- piperazin-1-yl) ethyl] -4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} benzamide 0.059 4 as in Example I- 291 (300 MHz, CDCb) δ 7.85 (s, 1H), 7.79 (d, 2H), 7.42 (d, 2H), 7.30 (dd, 1H), 7.07 (t, 1H ), 7.02 (d, 1H), 6.81 (bm, 1H), 6.13 (q, 1H), 5.42 (s, 2H), 3.80 (m, 2H), 3.62 (m, 2H), 3.53 (m, 2H), 2.68 (m, 2H), 2.52 (m, 4H), 2.10 (s, 3H), 1.87 (d, 3H), 575 [M + 1] 1- 301 οΑζχ, Ο fXLXÁJí TX, k 4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl) -N- (3pyrrolidin-1 -IIpropyl) - benzamide 0.064 4 as in Example I- 291 (300 MHz, CDCb) δ 8.71 (bm, 1H), 7.92 (m, 3H), 7.42 (d, 2H) 7.31 (dd, 1H), 7.06 (t, 1H) , 7.01 (s, 1H), 6.12 (q, 1H), 4.97 (s, 2H), 3.65 (m, 2H), 3.00 (m, 6H), 2.00 ( m, 6H), 1.87 (d, 3H), 533 [M + 1] I- 302 υζ Ih. 4- {6-amino-5- [1 (2,6-dichloro-3 fluoro-phenyl) -ethoxy] pyridin-3-yl) -N- (2morpholin-4-yl-ethyl) benzamide 0.071 4 as in Example I- 291 (300 MHz, CDCb) δ 7.90 (d, 1H), 7.79 (d, 2H), 7.44 (d, 2H), 7.31 (dd, 1H), 7.06 (t, 1H ), 7.01 (d, 1H), 6.83 (bm, 1H), 6.12 (q, 1H), 5.05 (s, 2H), 3.74 (m, 4H), 3.58 (m, 2H), 2.63 (m, 2H), 2.53 (m, 4H) 1.87 (d, 3H), 533 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 303 O Μ'-α (4- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - ((S) -3-aminopyrrolidin-1 -II) methanone 0.059 4 as in Example I- 291 (300 MHz, CDsOD) δ 7.76 (s, 1H), 7.54 (m, 1H), 7.42 (m, 4H), 7.24 (t, 1H), 7.04 (s, 1H), 6.22 (q, 1H), 4.82 (s, 2H), 3.76 (m, 1H), 3.68 (m, 2H), 3.52 (m, 1H), 2.28 (m, 1H), 1.92 (m, 3H), 1.75 (m, 1H), 1.42 (m, 1H), 491 [M + 1] 1- 304 nh ₂ yÓ Αλί (4- {6-amino-5- [1 (2,6-dichloro-3- fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((R) -3-aminopyrrolidin-1 -II) methanone 0.072 4 as in Example I- 291 (300 MHz, CDsOD) δ 7.76 (s, 1H), 7.54 (m, 1H), 7.42 (m, 4H), 7.24 (t, 1H), 7.04 (s, 1H), 6.22 (q, 1H), 4.82 (s, 2H), 3.76 (m, 1H), 3.68 (m, 2H), 3.52 (m, 1H), 2.28 (m, 1H), 1.92 (m, 3H), 1.75 (m, 1H), 1.42 (m, 1H), 491 [M + 1] 1- 305 (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-aminopiperidin-1 -II) methanone 0.18 4 as in Example I- 291 504 [M + 1] 1- 306 0 (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((S) -3-hydroxypyrrolidin-1 -II) methanone 0.024 4 as in Example I- 291 (300 MHz, CDsOD) δ 7.78 (d, 1H), 7.47 (m, 3H), 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.88 (s, 2H), 4.82 (dd, 1H), 4.15 (d, 1H), 3.53 (m, 2H) , 3.42 (m, 1H), 3.15 (m, 1H), 2.43 (m, 1H), 1.85 (m, 1H), 1.75 (d, 3H), 491 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 307 OH o Ó F (4- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((R) -3-hydroxypyrrolidin-1 -II) methanone 0.022 4 as in Example I- 291 (300 MHz, CDsOD) δ 7.80 (d, 1H), 7.47 (m, 3H), 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.89 (s, 2H), 4.82 (dd, 1H), 4.15 (d, 1H), 3.53 (m, 2H) , 3.42 (m, 1H), 3.15 (m, 1H), 2.43 (m, 1H), 1.85 (m, 1H), 1.75 (d, 3H), 491 [M + 1] 1- 308 O (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - ((R) -3hydroxymethylpyrrolidin-1 -II) methanone 0.033 4 as in Example I- 291 (300 MHz, CDsOD) δ 7.80 (d, 1H), 7.47 (m, 3H), 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.89 (s, 2H), 4.70 (m, 1H), 4.05 (m, 1H), 3.5 (m, 2H) , 3.32 (m, 1H), 2.43 (m, 1H), 1.85 (m, 3H), 1.75 (d, 3H), 1.15 (m, 1H), 505 [M + 1] 1- 309 Γ- 4- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -N- (2-ethylamino-ethyl) benzamide 0.04 4 as in Example I- 291 (300 MHz, CDCb) δ 9.55 (bm 1H), 8.80 (t, 1H), 7.95 (s, 1H), 7.58 (d, 2H), 7.55 (m, 3H) , 7.45 (t, 1H), 7.09 (d, 1H), 6.23 (q, 1H), 3.60 (q, 2H), 3.22 (m, 5H), 3.09 (m, 1H), 1.85 (d, 3H), 1.22 (dd, 6H) 519 [M + 1] 1- 310 4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (2pyrrolidin-1-yl-ethyl) benzamide 0.12 4 as in Example I- 291 (300 MHz, CDCb) δ 8.25 (bm, 1H), 7.90 (d, 1H), 7.82 (s, 2H), 7.34 (d, 2H), 7.25 (m, 1H ), 7.04 (t, 1H), 6.96 (s, 1H), 6.09 (q, 1H), 4.97 (s, 2H), 3.82 (m, 2H), 3.15 (m, 6H), 2.00 (m, 4H), 1.85 (d, 3H), 518 [M + 1] I- 311 0 LA _C1 3- {6-amino- 5- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -pyridin-3-yl} benzoic 3 as in the Example 211 420 [M-1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 312 (3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-methyl-piperazin1-yl) -methanone 0.062 4 (300 MHz, CDCb) δ 7.86 (s, 1H), 7.41 (m, 3H), 7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, 1H), 4.99 (s, 2H), 3.89 (m, 2H), 3.50 (m, 2H), 2.54 (m, 2H), 2.40 (m, 2H), 2.35 (s, 3H), 1.87 (d, 3H), 503 [M + 1] I- 313 ’ΆΧ 3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (1 methyl-piperidin-4yl) -benzamide 0.069 4 as in Example I- 312 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.76 (s, 1H), 7.67 (d, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 7.31 (dd, 1H), 7.05 (t, 1H), 7.01 (s, 1H), 6.28 (bd, 1H), 6.12 (q, 1H), 4.99 (s, 2H), 4.08 (m, 1H), 3.04 (m, 2H), 2.42 (s, 3H), 2.32 (m, 2H), 2.10 (m, 2H), 1.87 (d, 3H), 1.80 (m, 2H), 517 [M + 1] I- 314 s r- ° çro (3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((S) -2-pyrrolidin-1 ylmethyl-pyrrolidin1-yl ) -methanone 0.06 4 as in Example I- 312 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.40 (m, 4H), 7.29 (dd, 1H), 7.05 (t, 1H), 7.00 (s, 1H ), 6.12 (q, 1H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), 1.86 (d, 3H), 1.57 -2.18 (m, 11H), 559 [M + 1] I- 315 rrV ° ^Â N- [2- (4-acetyl- piperazin-1-yl) ethyl] -3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} benzamide 0.069 4 as in Example I- 312 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.83 (s, 1H), 7.65 (d, 1H), 7.46 (m, 2H), 7.32 (dd, 1H), 7.06 (t, 1H), 7.03 (s, 1H), 6.95 (bt, 1H), 6.12 (q, 1H), 5.08 (s, 2H), 3.66 (m, 4H), 3.50 (m, 2H), 2.73 (m, 2H), 2.52 (m, 4H), 2.09 (s, 3H), 1.87 (d, 3H), 576 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 316 (3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((S) -3-aminopyrrolidin-1 -II) methanone 0.048 4 as in Example I- 312 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.38 (m, 4H), 7.28 (m, 1H), 7.06 (t, 1H), 6.98 (s, 1H), 6.12 (q, 1H), 5.05 (s, 2H), 3.82 (m, 2H), 3.72 (m, 2H), 2.10 (m, 1H), 1.86 (d, 3H), 1.84 (m, 2H), 491 [M + 1] I- 317 t / 3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (3morpholin-4-ylpropyl) benzamide 0.059 4 as in Example I- 312 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.87 (s, 1H), 7.85 (d, 1H), 7.50 (m, 2H), 7.31 (dd, 1H ), 7.04 (m, 2H), 6.13 (q, 1H), 4.93 (s, 2H), 3.64 (m, 6H), 2.50 (m, 6H), 1.87 (d, 3H), 1.81 (m, 2H), 549 [M + 1] I- 318 f Γθ çro (3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((R) -2-pyrrolidin-1 ylmethyl-pyrrolidin-1 il) -methanone 0.13 4 as in Example I- 312 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.40 (m, 4H), 7.29 (dd, 1H), 7.05 (t, 1H), 7.00 (s, 1H ), 6.12 (q, 1H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), 1.86 (d, 3H), 1.57 -2.18 (m, 11H), 558 [M + 1] I- 319 Cl B 3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (2pyrrolidin-1-yl-ethyl) benzamide 0.1 4 as in Example I- 312 (300 MHz, CDCb) δ 7.86 (s, 1H), 7.82 (s, 1H), 7.73 (d, 1H), 7.46 (m, 4H), 7.22 (t, 1H), 7.04 (s, 1H), 6.95 (bt, 1H), 6.22 (q, 1H), 4.82 (s, 2H), 3.60 (m, 2H), 2.82 (m, 2H), 2.70 (m, 4H), 1.87 (d, 3H), 1.82 (m, 2H), 518 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 320 3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -N- (3pyrrolidin-1 -IIpropyl) -benzamide 0.13 4 as in Example I- 312 (300 MHz, CDCb) δ 8.66 (bt, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.61 (d, 1H), 7.42 (m, 2H ), 7.31 (dd, 1H), 7.05 (m, 2H), 6.14 (q, 1H), 4.88 (s, 2H), 3.65 (m, 2H), 2.71 (m, 2H), 2.56 (m, 4H), 1.87 (d, 3H), 1.80 (m, 2H), 1.71 (m, 4H), 531 [M + 1] 1- 321 3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -N- (2morpholin-4-yl-ethyl) benzamide 0.18 4 as in Example I- 312 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.84 (s, 1H), 7.66 (d, 1H), 7.46 (m, 2H), 7.32 (dd, 1H ), 7.05 (m, 2H), 6.88 (bt, 1H), 6.14 (q, 1H), 5.04 (s, 2H), 3.82 (m, 4H), 3.66 (m, 2H), 2.72 (t, 2H), 2.60 (m, 4H), 1.88 (d, 3H), 535 [M + 1] I- 322 (3- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-pyrrolidin-1 -IIpyrrolidin-1 -II) methanone 0.071 4 as in Example I- 312 (300 MHz, CDCb) δ 7.86 (s, 1H), 7.41 (m, 3H), 7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, 1H), 4.95 (s, 2H), 4.70 (m, 1H), 3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m , 1H), 2.65 (m, 4H), 2.28 (m, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, 2H), 559 [M + 1] I- 323 2- diethylamine ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro- 3- fluoro-phenyl) ethoxy] -pyridin-3-yl} - phenyl) -amide 0.08 9 (300 MHz, CDCb) δ 7.83 (s, 1H), 7.32 (m, 4H), 7.21 (d, 2H), 7.06 (t, 1H), 6.96 (s, 1H), 5.96 (q, 1H), 4.81 (s, 2H), 3.22 (m, 2H), 3.02 (m, 2H), 2.62 (m, 4H), 1.84 (d, 3H) 1.08 (t, 6H), 571 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 324 2- (4-hydroxypiperidin-1 -II) - ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro- 3- fluoro-phenyl) ethoxy] -pyridin-3-yl} - phenyl) -amide 0.059 9 as in Example I- 297 (300 MHz, CDCb) δ 7.81 (s, 1H), 7.31 (m, 3H), 7.25 (m, 3H), 7.07 (t, 1H), 6.96 (s, 1H), 6.11 (q, 1H), 4.95 (s, 2H), 3.76 (m, 1H), 3.25 (t, 2H), 2.92 (t, 2H), 2.79 (m, 2H), 2.25 (m, 2H), 1.93 (m, 2H), 1.86 (d, 3H), 1.62 (m, 2H), 583 [M + 1] 1- 325 TO 2-piperidin-1 -II ethanesulfonic acid (4- {6-amino5- [1- (2,6-dichloro3-fluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.089 9 as in Example I- 297 (300 MHz, CDCb) δ 7.84 (s, 1H), 7.32 (m, 4H), 7.21 (d, 2H), 7.06 (dd, 1H), 6.96 (s, 1H ), 6.11 (q, 1H), 4.88 (s, 2H), 3.24 (t, 2H), 2.89 (t, 2H), 2.48 (m, 4H), 1.86 (d, 3H), 1.62 (m, 4H), 1.49 (m, 2H), 558 [M + 1] 1- 326 ’7 2 (Cyclopropylmethylamino) -ethanesulfonic acid (4 {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.075 9 as in Example I- 297 (300 MHz, CDCb) δ 7.83 (s, 1H), 7.28 (m, 6H), 7.06 (dd, 1H), 6.96 (s, 1H), 6.11 (q, 1H), 4.91 (s, 2H), 3.22 (m, 4H), 2.50 (d, 2H), 1.86 (d, 3H), 0.84 (m 2H), 0.52 (m, 2H), 0.15 (m, 1H), 517 [M + 1] 1- 327 t F 2 - ((R) -3-hydroxypyrrolidin-1 -II) ethanesulfonic acid (4- {6-amino5- [1- (2-chloro-3,6difluor-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.093 9 as in Example I- 286 (300 MHz, CDCb) δ 7.83 (s, 1H), 7.32 (m, 5H), 7.05 (m, 3H), 5.95 (q, 1H), 4.84 (s, 2H), 4.43 (m, 1H), 3.25 (m, 2H), 3.02 (m, 3H), 2.84 (m, 1H) , 2.53 (m, 1H), 2.30 (m, 1H), 2.22 (m, 1H), 1.84 (d, 3H), 1.81 (m, 1H), 553 [M + 1] 1- 328 F 2cyclopropylamino acid ethanesulfonic (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.16 9 as in Example I- 286 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.38 (d, 2H), 7.24 (m, 2H), 7.18 (m, 3H), 5.95 (q, 1H), 4.89 (s, 2H), 3.22 (m, 4H), 2.14 (m, 1H), 1.85 (d, 3H), 0.50 (m, 2H), 0.38 (m, 2H), 523 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 329 XXV 2-diethylamino acid ethanesulfonic (4- {6-amino5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.095 9 as in Example I- 286 (300 MHz, CDCb) δ 7.84 (s, 1H), 7.34 (d, 2H), 7.23 (m, 3H), 7.02 (m, 3H), 5.96 (q, 1H), 4.81 (s, 2H), 3.22 (m, 2H), 3.02 (m2H), 2.62 (m, 4H), 1.84 (d, 3H), 1.08 (t, 6H), 539 [M + 1] 1- 330 Áop 4- {6-amino- 5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} benzoic 3 as in the Example 211 405 [M + 1] 1- 331 JPo φφΑτ F 4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.13 4 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.80 (d, 2H), 7.46 (d, 2H), 7.05 (m, 3H), 6.87 (m, 1H ), 5.97 (q, 1H), 4.97 (s, 2H), 3.75 (m, 4H), 3.58 (m, 2H), 2.60 (m, 6H), 1.84 (m, 3H), 517 [M + 1] I- 332 0 4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (1-methylpiperidin-4-yl) benzamide 0.079 4 as in Example I- 331 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.78 (d, 2H), 7.45 (d, 2H), 7.05 (m, 4H), 5.98 (q, 1H), 4.90 (s, 2H), 4.00 (m, 1H), 2.88 (m, 2H), 2.32 (s, 3H), 2.18 (m, 2H), 2.08 (m, 2H), 1.84 (d, 3H), 1.57 (m, 2H), 501 [M + 1] I- 333 hi> 0 XAJU líl ° ^NH · F (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) ((R) -2-pyrrolidin1 -ylmethyl-pyrrolidin1-yl) -methanone 0.067 4 as in Example I- 331 (300 MHz, CDCb) δ 7, 90 (s, 1H), 7.54 (m, 2H), 7.42 (d, 2H), 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H ), 3.50 (m, 2H), 3.74 (m, 4H), 1.84 (d, 3H), 157-2.18 (m, 11H) 541 [M + 1] I- 334 NH, oA ô χχ (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((R) -3amino-pyrrolidin-1yl) -methanone 0.089 4 as in Example I- 331 (300 MHz, CDCb) δ 7.68 (m, 5H), 7.25 (m, 3H), 6.27 (m, 1H), 4.88 (s, 2H), 3.75 (m, 5H), 3.31 (m, 2H), 2.44 (m, 1H), 2.17 (m, 1H), 1.93 (m, 3H), 473 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 335 0 (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((3R, 5S) 3,5-dimethyl-piperazin-1 -II) methanone 0.09 4 as in Example I- 331 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.42 (m, 4H), 7.05 (m, 3H), 5.97 (q, 1H), 4.86 (s, 2H), 4.62 (m, 1H), 3.65 (m, 1H), 2.88 (m, 2H), 2.68 (m, 1H), 2.41 (m, 1H), 1.84 (d, 3H), 1.64 (m, 1H), 1.05 (m, 6H), 501 [M + 1] 1- 336 X F 4- {6-amino-5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (3-pyrrolidin-1 -IIpropyl) -benzamide 0.09 4 as in Example I- 331 (300 MHz, CDCb) δ 9.00 (s, 1H), 7.92 (s, 1H), 7.83 (d, 2H), 7.42 (d, 2H), 7.09 (m, 2H ), 7.01 (m, 1H), 5.96 (q, 1H), 4.89 (s, 2H), 3.60 (m, 2H), 2.75 (m, 2H), 2.62 (m, 4H), 1.85 (m, 7H), 515 [M + 1] 1- 337 ÂXJÇ F (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.09 4 as in Example I- 331 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.53 (m, 2H), 7.43 (d, 2H), 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, 1H), 3.58 (m, 2H), 3.00 (m, 4H), 1.84 (d, 3H), 1.70-2.18 (m, 10H) 541 [M + 1] 1- 338 AAJU A “F (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-methylpiperazin-1 -II) methanone 0.077 4 as in Example I- 331 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.44 (m, 4H), 7.07 (m, 3H), 5.95 (q, 1H), 4.87 (s, 2H), 3.60 (m, 4H), 2.43 (m, 4H), 2.3 (s, 3H), 1.84 (d, 3H) , 487 [M + 1] 1- 339 I 1 µ. (fyvy yk _a «Η. (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-pyrrolidin1 -yl-piperidin-1 -II) methanone 0.062 4 as in Example I- 331 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.42 (m, 4H), 7.02 (m, 3H), 6.00 (q, 1H), 4.87 (s, 2H), 4.64 (m, 1H), 3.85 (m, 1H), 2.99 (m, 2H), 2.67 (m, 4H) , 2.38 (m, 1H), 1.90 (m, 9H), 1.62 (m, 2H), 541 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 340 4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.086 4 as in Example I- 331 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.86 (d, 2H), 7.45 (d, 2H), 7.10 (m, 3H), 7.01 (m, 1H ), 5.98 (q, 1H), 4.90 (s, 2H), 3.60 (m, 2H), 2.80 (m, 2H), 2.68 (m, 4H), 1.85 (m, 7H), 501 [M + 1] 1- 341 0 Ai ώ ‘LfAc NH, f (4- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((S) -3amino-pyrrolidin-1yl) -methanone 0.075 4 as in Example I- 331 (300 MHz, CDCb) δ 7.76 (s 1H), 7.67 (m, 2H), 7.59 (d, 2H), 7.42 (s, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 6.27 (m, 1H), 4.86 (s, 2H), 3.75 (m, 5H) , 3.31 (m, 2H), 2.44 (m, 1H), 2.14 (m, 1H), 1.95 (m, 3H), 473 [M + 1] I- 342 çf ” ^{N NH} l Ύ 'Cl * F 3- {6-amino- 5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} benzoic as in Example 211 405 [M + 1] I- 343 F (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((3S, 5S) 3,5-dimethylpiperazin-1 -II ) methanone 0.16 4 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.43 (m, 2H), 7.30 (m, 2H) 7.10 (m, 2H), 6.95 (m, 1H) , 5.97 (q, 1H), 4.87 (s, 2H), 4.65 (m, 1H), 3.60 (m, 1H), 2.72 (m, 3H), 2.41 ( m, 1H), 2.01 (s, 1H), 1.84 (d, 3H), 1.17 (m, 3H), 0.98 (m, 3H), 501 [M + 1] I- 344 (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((R) -3amino-pyrrolidin-1yl) -methanone 0.12 4 as in Example 343 (300 MHz, CDCb) δ 7.65 (m, 5H), 7.42 (s, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 6.27 (m, 1H ), 4.85 (s, 2H), 3.75 (m, 5H), 3.31 (m, 2H), 2.44 (m, 1H), 2.16 (m, 1H), 1.93 (m, 3H), 473 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 345 F 3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (1-methylpiperidin-4-yl) benzamide 0.2 4 as in Example 343 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.78 (s, 1H), 7.67 (d, 1H) 7.45 (m, 2H), 7.00 (m, 3H) , 6.15 (bd, 1H), 5.98 (q, 1H), 4.08 (m, 1H), 2.97 (m, 2H), 2.38 (s, 3H), 2.27 ( m, 2H), 2.10 (m, 2H), 1.84 (d, 3H), 1.74 (m, 2H), 501 [M + 1] 1- 346 çX y-a F (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-methylpiperazin-1 -II) methanone 0.19 4 as in Example 343 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.42 (m, 3H), 7.30 (m, 2H), 7.09 (m, 2H), 7.00 (m, 1H ), 5.95 (q, 1H), 4.87 (s, 2H), 3.83 (m, 2H), 3.47 (m, 2H), 2.51 (m, 2H), 2.33 (m, 5H), 1.84 (d, 3H), 487 [M + 1] 1- 347 γ'α * ¹ 'F 3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (3-pyrrolidin-1 yl) -benzamide 0.21 4 as in Example 343 (300 MHz, CDCb) δ 8.69 (s, 1H), 7.91 (m, 2H), 7.65 (d, 1H), 7.42 (m, 2H), 7.00 (m, 3H) 5.99 (q, 1H), 4.85 (s, 2H), 3.60 (m, 2H), 2.76 (m, 2H), 2.63 (m, 4H), 1.84 (d, 3H), 1.77 (m, 6H), 515 [M + 1] 1- 348 3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.2 4 as in Example 343 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.86 (s, 1H), 7.70 (d, 1H), 7.50 (m, 2H), 7.00 (m, 4H), 5.99 (q, 1H), 4.86 (s, 2H), 3.60 (m, 2H), 2.78 (m, 2H), 2.63 (m, 4H), 1.85 (m, 7H), 501 [M + 1] 1- 349 φύ? (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((S) -3amino-pyrrolidin-1yl) -methanone 0.13 4 as in Example 343 (300 MHz, CDCb) δ 7.70 (m, 5H), 7.42 (s, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 6.27 (m, 1H ), 4.85 (s, 2H), 3.75 (m, 5H), 3.31 (m, 2H), 2.66 (m, 1H), 2.44 (m, 1H), 1.93 (m, 3H), 473

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 350 çA ⁷ A- 3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.39 4 as in Example 343 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.84 (s, 1H), 7.65 (d, 1H), 7.46 (m, 2H), 7.05 (m, 3H ), 6.83 (bs, 1H), 5.97 (q, 1H), 4.91 (s, 2H), 3.74 (m, 4H), 3.58 (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H), 1.84 (m, 3H), 517 [M + 1] 1- 351 F (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((R) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.23 4 as in Example 343 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.45 (m, 4H), 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, 1H), 3.64 (m, 1H), 3.44 (m, 1H), 2.64 (m, 4H), 1.83 (d, 3H), 1.70-2.18 (m, 10H) 541 [M + 1] I- 352 O çXó «A (3- {6-amino-5- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((S) -2-pyrrolidin-1-ylmethylpyrrolidin-1 - II) methanone 0.15 4 as in Example 343 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.45 (m, 4H), 7.09 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, 1H), 3.45 (m, 2H), 2.75 (m, 4H), 1.84 (d, 3H) , 1.70-2.18 (m, 10H) 541 [M + 1] I- 353 P ? TFA 0 AA 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] 5- [4- (2-morpholin-4yl-ethoxy) -phenyl] pyridin-2-ylamine 0.23 3 as in Example I-2 I- 354 OAO φΧΧ * 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] 5- [3- (2-morpholin-4yl-ethoxy) -phenyl] pyridin-2-ylamine 0.22 3 as in Example I-2

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 355 O L JL NH, 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [4- (2-pyrrolidin1 -yl-ethoxy) -phenyl] pyridin-2-ylamine 0.068 3 as in Example I-2 (400 MHz, DMSO- de): d 7.74 (d, J = 2.0 Hz, 1H), 7.53 (m, 1H), 7.44 (m, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 1.6 Hz, 1H), 6.11 (m, 1H), 5.79 (s, 2H), 4.30 (m, 2H), 3.5 ( m, 6H), 1.90 (m, 4H), 1.807 (d, J = 6.7 Hz, 3H), 491 [M + 1] 1- 356 '* Ν * Λ i L 0 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] - 5- [4- [2- (1-methylpyrrolidin-2-yl) ethoxy] -phenyl} pyridin-2-ylamine 0.079 3 as in Example I-2 (400 MHz, DMSO- de): d 7.73 (s, 1H), 7.54 (m, 1H), 7.44 (m, 2H), 7.284 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.88 (s , 1H, pyridine-H), 6.10 (m, 1H), 5.78 (s, 2H), 4.7 (m, 1H), 3.3 (m, 2H), 3.1 (m, 2H), 2.77 (s, 3H), 2.3 (m, 6H), 1.81 (d, J = 6.2 Hz, 3H, 504 [M + 1] 1- 357 0 * ^ ° L ⁰ Hrtj F 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [4- (2-morpholin-4yl-ethoxy) -phenyl] pyridin-2-ylamine 0.13 3 as in Example i-2 (400 MHz, DMSO- de): 7.72 (d, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 7.03 (m , 3H), 6.23 (q, 1H), 4.35 (m, 2H) 3.95 (m, 1H), 3.03.8 (m, 9H), 1.851 (d, 3H), 506 [M + 1] 1- 358 Çr ~ O 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [3- (2-morpholin-4yl-ethoxy) -phenyl] pyridin-2-ylamine 0.22 3 as in Example i-2 (400 MHz, DMSO- de): d 7.82 (d, 1H), 7.53 (q, 1H), 7.46 (t, 1H), 7.33 (t, 1H), 7.03 (m, 3H), 6.95 (dd, 1H), 6.24 (q, 1H), 4.38 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.61 (m, 2H), 3.5 (m, 2H), 3.25 (m, 2H), 1.851 (d, 3H), 506 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 359 JL NM. 1- (4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenoxy) -3-morpholin-4-ylpropan-2-ol 0.045 3 as in Example I-2 (400 MHz, DMSO- de): d 7.73 (d, J = 1.6 Hz, 1H), 7.56 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.28 (d, J = 6.7 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 2.0 Hz, 1H), 6.11 (m, 1H), 5.75 (s, 2H), 4.88 (d, J = 2.0 Hz, 1H), 3.96 (m, 3H), 3.57 (t, J = 4.3 Hz, 4H), 2.42 (m, 6H), 1.81 (d, J = 6.7 Hz, 3H), 536 [M + 1] 1- 360 Αχ pJLâXj rr ° τ ÇA _a 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [4- (2-ethylamino-ethoxy) phenyl] -pyridin-2-amine 0.033 3 as in Example I-2 (400 MHz, DMSO- de): d 7.73 (d, J = 1.6 Hz, 1H), 7.56 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 1.6 Hz, 1H), 8.11 (m, 1H), 5.75 (s, 2H), 4.02 (t, J = 6.2 Hz, 2H), 2.756 (m, 2H), 2.55 (m, 4H), 1.81 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.0 Hz, 6H), 494 [M + 1] 1- 361 0¾ L JL NH. ^ <^ 0 ¹ 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] - 5- [4- (1-methylpiperidin-3ylmethoxy) -phenyl] pyridin-2-ylamine 0.043 3 as in Example I-2 (400 MHz, DMSO- de): d 7.73 (d, J = 2.0 Hz, 1H), 7.53 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 1.6 Hz, 1H), 8.10 (m, 1H), 5.75 (s, 2H), 3.831 (m, 2H), 2.81 (m, 1H), 2.62 (s, 1H), 2153 (s, 3H) 1.95 (m, 3H), 1.81 (d, J = 6.7 Hz, 3H), 1.72 (m, 4H), 504 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 362 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [4- (2diisopropylaminoethoxy) -phenyl] pyridin-2-ylamine 0.052 3 as in Example I-2 (400 MHz, DMSO- de): d 7.73 (d, J = 2.0 Hz, 1H), 7.53 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.27 (m, 2H), 6.91 (m, 2H), 6.88 (d, J = 2.0 Hz, 1H), 6.11 (m, 1H), 5.74 (s, 2H), 3.88 (t, J = 6.7 Hz, 2H), 3.02 (m, 2H), 2.76 (t, J = 6.7 Hz, 2H), 1.81 (d, J = 6.7 Hz, 3H), 0.986 (m, 12H), 520 [M + 1] 1- 363 0 Y / A · '' THE 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] 5- [4- (1-methylpiperidin-4-yloxy) phenyl] -pyridin-2ylamine 0.052 3 (400 MHz, DMSO- de): d 7.66 (d, J = 1.6 Hz, 1H), 7.49 (m, 1H), 7.377 (t, J = 8.2 Hz, 1H), 7.20 (m, 2H), 6.87 (m, 2H), 6.81 (d, J = 1.6 Hz, 1H), 6.04 (m, 1H), 5.68 ( s, 2H), 4.30 (m, 1H), 2.55 (m, 2H), 2.12 (m, 5H), 1.84 (m, 2H), 1.74 (d, J = 6.7 Hz, 3H), 1,, 7 (m, 2H), 490 [M + 1] 1- 364 t- Η ^ ⁸ * 0 F N- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl) phenyl) methanesulfonamide 0.1 3 as in Example I- 135 454 [M + 1] 1- 365 0 lAji 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- [4- (1,1dioxo1lambda * 6 * isothiazolidin-2-yl) phenyl] -pyridin-2ylamine 0.14 3 as in Example I- 240 478 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 366 8 IL r N- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl) phenyl) methanesulfonamide 0.076 3 as in Example I- 135 (300 MHz, CDCb) δ 9.75 (s, 1H), 7.88 (d, 1H), 7.55 (q, 1H), 7.45 (t, 1H), 7.35 (d, 2H), 7.18 (d, 2H), 6.9 (d, 1H), 6.10 (q, 1H), 5.85 (s, 2H), 2.99 (s, 3H), 1.80 (d, 3H), 470 [M + 1] 1- 367 0 n o OC _{c |} NH, 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5-phenylpyridin-2-ylamine 0.5 3 (300 MHz, CDCb) δ 7.80 (d, 1H), 7.55 (q, 1H), 7.45 (t, 1H), 7.35 (dd, 4H), 7.25 (m, 1H ), 6.95 (d, 1H), 6.12 (q, 1H), 5.85 (s, 2H), 1.80 (d, 3H), 377 [M + 1] 1- 368 hJÍj TFA XAJu CC í. N- (4- {6-amino-5 [(R) -1- (2-chloro3,6-difluoro-phenyl) ethoxy] -pyridin-3-yl) phenyl) methanesulfonamide 0.066 3 as in Example I- 135 (300 MHz, CDCb) δ 9.80 (s, 1H), 7.70 (d, 1H), 7.43 (m, 3H), 7.30 (ddd, 1H), 7.25 (d, 1H), 7.18 (m, 2H), 6.10 (q, 1H), 2.95 (s, 3H), 1.75 (d, 3H), 454 [M + 1] 1- 369 Sn Ϋ <A _{0 |} HH, 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5-thiophen-3-ylpyridin-2-ylamine 0.055 3 383 [M + 1] 1- 370 yes Py ^ oXpi M-C1 ·> 5-benzo [b] thiophen2-yl-3- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-2-ylamine 1.95 3 433 [M + 1] 1- 371 LX _to NH. 4-methylpiperazine-1-carboxylic acid (4- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.057 10 (300 MHz, CDCb) δ 7.71 (s, 1H), 7.40 (d, 2H), 7.32- 7.23 (m, 3H), 7.06 (t, 1H), 6.99 (s, 1H), 6 , 77 (bs, 1H), 6.11 (q, 1H), 5.62 (s, 2H), 3.60 (m, 4H), 2.57 (m, 4H), 2.40 (s, 3H), 1.87 (d, 3H), 518 [M + 1] I- 372 XX JLX Pl »1 Us _c , 1- (4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) 3- (2-pyrrolidin-1-IIethyl) -urea 0.21 10 as in Example I- 371 532 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 373 ivy NH, F 1- (4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) 3- (2-hydroxy-ethyl) urea 0.064 10 as in Example I- 371 (300 MHz, CDCb) δ 7.68 (s, 2H) 7.45 (m, 2H), 7.36 (d, 2H), 7.25 (m, 2H), 6.95 (s, 2H) , 6.55 (q, 1H), 4.86 (s, 2H), 3.63 (t, 2H), 3.31 (m, 3H), 1.87 (d, 3H), 479 [M + 1] 1- 374 0 1- (4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) 3- (2-hydroxy-ethyl) urea 0.062 10 as in Example I- 371 (300 MHz, CDCb) δ 7.88 (s, 1 H), 7.55 (m, 3H), 7.35 (d, 2H), 7.23 (m, 3H), 6.95 (s, 1H), 6.55 (q, 1H), 4.86 (s, 2H), 3.71 (t, 2H), 3.31 (m, 6H), 2.51 (m, 4H) 1.86 (d, 3H), 548.2 [M + 1] 1- 375 X âaO ÇL, k (R) -3amino-pyrrolidine-1-carboxylic acid (4 {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.053 10 as in Example I- 371 (300 MHz, CDCb) δ 7.65 (m, 4H), 7.31 (m, 3H), 7.19 (m, 2H), 6.37 (m, 1H), 4.87 (s, 2H), 3.95 (m, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.31 (m, 2H) , 2.45 (m, 1H), 2.18 (m, 1H), 1.95 (d, 3H), 503.8 [M + 1] 1- 376 HH 7 (S) -3amino-pyrrolidine-1-carboxylic acid (4 {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.052 10 as in Example I- 371 (300 MHz, CDCb) δ 7.65 (m, 4H), 7.31 (m, 3H), 7.19 (m, 2H), 6.37 (m, 1H), 4.87 (s, 2H), 3.95 (m, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.31 (m, 2H) , 2.45 (m, 1H), 2.18 (m, 1H), 1.95 (d, 3H), 504.1 [M + 1] 1- 377 1- (4- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) - 3- (1-methylpiperidin-4-yl) urea 0.04 10 as in Example I- 371 534 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 378 íjx / íj F 1- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -3- (1-methylpiperidin-4-yl) urea 0.038 10 as in Example I- 371 518 [M + 1] 1- 379 There is THE (R) -3amino-pyrrolidine-1-carboxylic acid (4 {6-amino-5- [1 (3,6-difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -amide 0.069 10 as in Example I- 371 488 [M + 1] 1- 380 Ύ / Ο ^- 'κα t ⁿ F (S) -3amino-pyrrolidine-1-carboxylic acid (4 {6-amino-5- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.075 10 as in Example I- 371 488 [M + 1] 1- 381 mA'U ^ ' ^cm 1- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -3- (2-hydroxyethyl) -urea 0.11 10 as in Example I- 371 (300 MHz, CDCb) δ 7.69 (d, 2H), 7.37 (d, 2H), 7.25 (d, 2H), 7.15 (m, 2H), 7.09 (d, 2H ), 6.00 (q, 1H), 4.86 (s, 2H), 3.63 (t, 2H), 3.32 (m, 3H), 1.83 (d, 3H), 463 [M + 1] I- 382 ? 4-methylpiperazine-1carboxylic acid (4- {6 amino-5- [1- (2chloro-3,6-difluorphenyl) -ethoxy] pyridin-3-yl) -phenyl) amide 0.082 10 as in Example I- 371 (300 MHz, CDCb) δ 7.78 (s, 1H), 7.41 (d, 2H), 7.29 (d, 2H), 7.09 (s, 1H), 7.05 (m, 1H ), 6.95 (m, 1H), 6.56 (bs, 1H), 6.00 (q, 1H), 5.25 (s, 2H), 3.58 (m, 4H), 2.53 (m, 4H), 2.38 (s, 3H), 1.84 (d, 3H), 502 [M + 1] I- 383 1- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -3- (2pyrrolidin-1-yl-ethyl) urea 0.11 10 as in Example I- 371 516 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 384 XA-O 1- (4- {6-amino-5 [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -3- (2morpholin-4-yl-ethyl) urea 0.13 10 as in Example I- 371 (300 MHz, CDCb) δ 7.83 (d, 1H), 7.29 (m, 5H), 7.00 (m, 4H), 5.94 (q, 1H), 4.87 (bs, 2H ), 3.67 (m, 4H), 3.38 (m, 2H), 2.52 (m, 4H), 1.86 (d, 3H), 533.7 [M + 1] 1- 385 Q Vo ^NH > (R) -2pyrrolidin-1-ylmethylpyrrolidine-1 carboxylic acid (4- {6 amino-5- [1- (2chloro-3,6-difluorphenyl) -ethoxy] pyridin-3-yl} -phenyl) amide 0.13 10 as in Example I- 371 (300 MHz, CDCb) δ 7.93 (s, 1H), 7.67 (d, 2H), 7.27 (d, 2H), 6.95 (m, 4H), 6.70 (q, 1H ), 4.84 (s, 2H), 3.85 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.90 (m, 4H), 2.65 (m, 4H), 2.10 (m, 3H), 1.85 (d, 3H), 1.91.7 (m, 3H), 555.8 [M + 1] 1- 386 Ά (3- {6 amino-5- [1- (2,6dichloro-phenyl) ethoxy] -pyridin-3-yl} benzoic acid 3 as in Example I- 211 403 [M + 1] 1- 387 çp óX (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((3R, 5S) 3,5-dimethyl-piperazin-1 -II ) methanone 0.16 4 (300 MHz, CDCb) δ 7.86 (s, 1H), 7.39 (m, 4H), 7.31 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, 1H), 4.93 (s, 2H), 4.65 (m, 1H), 3.56 (m, 1H) , 2.95 (m, 1H), 2.79 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 1.84 (d, 3H), 1.95 (m, 1H), 1.25 (d, 3H), 1.17 (d, 3H), 501 [M + 1] 1- 388 X (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-pyrrolidin1 -yl-piperidin-1 -II) methanone 0.1 4 as in Example I- 387 (300 MHz, CDCb) δ 7.85 (s, 1H), 7.39 (m, 4H), 7.32 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, 1H), 4.90 (s, 2H), 4.65 (m, 1H), 3.65 (m, 1H), 3.05 (m, 2H), 2.80 (m, 1H), 2.65 (m, 4H), 2.30 (m, 1H), 2.05 (m, 1H), 1.86 (d, 3H), 1.81 (m, 3H), 1.52 (m, 4H), 539 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 389 (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.13 4 as in Example I- 387 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.45 (m, 3H), 7.32 (d, 2H ), 7.15 (t, 1H), 7.06 (s, 1H), 6.99 (bm, 1H), 6.16 (q, 1H), 4.93 (s, 2H), 3.61 (m, 2H), 2.78 (m, 2H) 2.63 (m, 4H), 1.87 (d, 3H), 1.82 (m, 4H), 501 [M + 1] 1- 390 έάΡ (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.12 4 as in Example I- 387 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.82 (s, 1H), 7.65 (d, 1H), 7.48 (m, 3H), 7.32 (d, 2H ), 7.15 (t, 1H), 7.06 (s, 1H), 6.78 (bm, 1H), 6.16 (q, 1H), 4.95 (s, 2H), 3.73 (m, 4H), 3.59 (m, 2H), 2.62 (m, 2H), 2.51 (m, 4H ), 1.87 (d, 3H), 517 [M + 1] 1- 391 (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} ((S) -2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl) -methanone 0.098 4 as in Example I- 387 (300 MHz, CDCb) δ 7.86 (d, 1H), 7.37 (m, 4H), 7.30 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, 1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.84 (d , 3H), 1.70-2.0 (m, 10H) 541 [M + 1] I- 392 çVo Μγ The (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} N- (3-pyrrolidin-1 -IIpropyl) -benzamide 0.072 4 as in Example I- 387 (300 MHz, CDCb) δ 8.60 (bm, 1H), 7.89 (s, 1 H), 7.65 (d, 1H), 7.45 (m, 3H), 7.32 (d, 2H), 7.15 (t, 1H), 7.04 (s, 1H), 6.17 (q, 1H), 4.89 (s, 2H), 3.62 (m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.86 (d, 3H), 1.83 (m, 2H), 1.79 (m, 4H), 513 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 393 N- [2- (4-acetylpiperazin-1 -II) ethyl) -3- {6-amino-5 [1- (2,6-dichlorophenyl-ethoxy] pyrridin-3-yl} benzamide 0.079 4 as in Example I- 387 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.81 (s, 1H), 7.63 (d, 1H), 7.48 (m, 3H), 7.32 (d, 2H ), 7.15 (t, 1H), 7.06 (s, 1H), 6.69 (bm, 1H), 6.16 (q, 1H), 4.94 (s, 2H), 3.65 (m, 4H), 3.50 (m, 2H), 2.62 (m, 2H), 2.52 (m, 4H ), 2.09 (s, 3H), 1.87 (d, 3H), 556 [M + 1] 1- 394 (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} - N- (1-methylpiperidin-4-yl) benzamide 0.061 4 as in Example I- 387 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.73 (s, 1 H), 7.65 (d, 1H) 7.50 (d, 1H), 7.43 (t, 1H), 7.32 (d, 2H), 7.16 (t, 1H), 7.04 (s, 1H), 6.15 (m, 1H), 6.05 (bd, 1H), 4.92 (s, 2H), 4.03 (m, 1H), 2.94 (m, 2H), 2.38 (s, 3H), 2.26 (m, 2H), 2.09 (m, 2H), 1.86 (d, 3H), 1.70 (m, 2H), 499 [M + 1] 1- 395 ώι έφτ (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-methylpyrerazin-1 -II) methanone 0.058 4 as in Example I- 387 (300 MHz, CDCb) δ 7.85 (s, 1H), 7.40 (m, 4H), 7.30 (d, 2H), 7.16 (t, 1H), 7.02 (s, 1H), 6.15 (m, 1H), 4.93 (s, 2H), 3.82 (m, 2H), 3.45 (m, 2H) , 2.52 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H), 1.86 (d, 2H), 487 [M + 1] 1- 396 p y-O Çr Ó (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl - ((R) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.18 4 as in Example I- 387 (300 MHz, CDCb) δ 7.86 (d, 1H), 7.37 (m, 4H), 7.30 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, 1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.84 (d , 3H), 1.70-2.0 (m, 10H) 541 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 397 eox HO (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl - ((S) -3amino-pyrrolidin-1yl) -methanone 0.055 4 as in Example I- 387 (300 MHz, CDsOD) δ 7.74 (s, 1H), 7.69- 7.43 (m, 6H), 7.32 (t, 1H), 7.22 (s, 1H), 6.42 (m, 1H), 4.05-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H ), 2.18 (m, 1H), 1.90 (d, 3H), 471 [M + 1] 1- 398 HCt (3- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl - ((R) -3amino-pyrrolidin-1yl) -methanone 0.072 4 as in Example I- 387 (300 MHz, CDsOD) δ 7.74 (s, 1H), 7.69- 7.43 (m, 6H), 7.32 (t, 1H), 7.22 (s, 1H), 6.42 (m, 1H), 4.05-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H ), 2.18 (m, 1H), 1.90 (d, 3H), 471 [M + 1] 1- 399 O ^ OH O OXY 4- {6-amino- 5- [1- (2,6-dichlorophenyl) -ethoxy] pyridin-3-yl} benzoic 4 as in Example I- 387 403 [M + 1] 1- 400 ϊΐώ CÇ '', 4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.059 4 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.79 (d, 2H), 7.43 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.87 (bm, 1H), 6.15 (q, 1H), 4.93 (s, 2H), 3.56 (m, 2H), 2.72 (m, 2H), 2.58 (m, 4H), 1.87 (d, 3H), 1.80 (m, 4H), 501 [M + 1] 1- 401 4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.073 4 as in Example I- 400 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.79 (d, 2H), 7.44 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.03 (s, 1H), 6.77 (bm, 1H), 6.15 (q, 1H), 4.95 (s, 2H), 3.74 (m, 4H), 3.57 (m, 2H), 2.61 (m, 2H), 2.52 (m, 4H), 1.87 (d, 3H), 515 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 402 .,.O T LXo, X (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.068 4 as in Example I- 400 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.52 (m, 2H), 7.39 (d, 2H), 7.31 (d, 2H) 7.15 (t, 1H), 7.01 (s, 1H), 6.15 (q, 1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, 10H) 539 [M + 1] 1- 403 0 XAJU il ⁰ MC, «Η. (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl-N- (1-methylpiperidin-4-yl) benzamide 0.062 4 as in Example I- 400 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.76 (d, 2H), 7.42 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (q, 1H), 5.97 (bd, 1H), 4.94 (s, 2H), 4.03 (m, 1H), 2.85 (m, 2H), 2.32 (s, 3H), 2.18 (m, 2H), 2.06 (m, 2H), 1.86 (d, 3H), 1.60 (m, 2H), 501 [M + 1] 1- 404 ANH Q AXp (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((3R, 5S) - 3,5-dimethyl-piperazin-1 -II) methanone 0.052 4 as in Example I- 400 (300 MHz, CDCb) δ 7.88 (s, 1H), 7.41 (m, 4H), 7.32 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (q, 1H), 4.92 (s, 2H), 4.62 (m, 1H), 3.66 (m, 1H), 2.82 (m, 2H), 2.68 (m, 1H), 2.40 (m, 1H), 1.87 (d, 3H), 1.65 (m, 1H), 1.15 (d, 3H), 0.98 (d, 3H), 499 [M + 1] 1- 405 N- [2- (4-acetylpiperazin-1 -II) ethyl] -4- {6-amino-5 [1- (2,6-dichlorophenyl) -ethoxy] pyridin-3-yl) benzamide 0.062 4 as in Example I- 400 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.78 (d, 2H), 7.44 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.03 (s, 1H), 6.69 (bm, 1H), 6.15 (q, 1H), 4.96 (s, 2H), 3.66 (m, 2H), 3.61 (m, 2H), 3.50 (m, 2H), 2.62 (m, 2H), 2.52 (m, 4H), 2.10 (s, 3H), 1.87 (d, 3H), 556 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 406 0 (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) -N- (3pyrrolidin-1 -IIpropyl) -benzamide 0.061 4 as in Example I- 400 (300 MHz, CDCb) δ 8.80 (bm, 1H), 7.90 (s, 1H), 7.79 (d, 2H), 7.40 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (q, 1H), 4.91 (s, 2H), 3.62 (m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.87 (d, 3H), 1.85 (m, 4H), 1.25 (m, 2H), 513 [M + 1] 1- 407 φΤ 0 άΑ HCI (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((S) -3aminopyrrolidin-1yl) -methanone 0.05 4 as in Example I- 400 (300 MHz, CDsOD) δ 7.74- 7.24 (m, 9H), 6.39 (m, 1H), 4.05- 3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H), 2.18 (m, 1H), 1.90 (d, 3H) 471 [M + 1] 1- 408 uo HCt (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((R) -3amino-pyrrolidin-1II) - methanone 0.049 4 as in Example I- 400 (300MHZ, CDsOD) δ 7.74- 7.24 (m, 9H), 6.39 (m, 1H), 4.053.60 (m, 4H), 3.50 (m, 1H), 2.50 ( m, 1H), 2.18 (m, 1H), 1.90 (d, 3H), 471 [M + 1] 1- 409 Q Λ> òA (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - ((R) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.081 4 as in Example I- 400 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.52 (m, 2H), 7.39 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.01 (s, 1H), 6.15 (q, 1H), 4.91 (s, 2H), 4.45 (m, 1H) , 3.41 (m, 2H), 2.70 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, 10H) 539 [M + 1] 1- 410 (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-pyrrolidin1 -yl-piperidin-1 -II) methanone 0.055 4 as in Example I- 400 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.39 (m, 4H), 7.32 (d, 2H), 7.17 (t, 1H), 7.01 (s, 1H), 6.15 (q, 1H), 4.91 (s, 2H), 4.60 (m, 1H), 3.76 (m, 1H), 3.00 (m, 2H), 2.60 (m, 4H), 2.28 (m, 1H), 1.95 (m, 2H), 1.86 (d, 3H), 1.81 (m, 4H), 1.56 (m, 2H), 541 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 411 T (4- {6-amino-5- [1 (2,6-dichloro-phenyl) ethoxy] -pyridin-3-yl} phenyl) - (4-methylpiperazin-1 -II) methanone 0.053 4 as in Example I- 400 (300 MHz, CDCb) δ 7.87 (s, 1H), 7.40 (m, 4H), 7.31 (d, 2H), 7.15 (t, 1H), 7.01 (s, 1H), 6.15 (q, 1H), 4.92 (s, 2H), 3.78 (m, 2H), 3.52 (m, 2H) , 2.41 (m, 4H), 2.34 (s, 3H), 1.86 (d, 3H), 487 [M + 1] I- 412 ? F (S) -2pyrrolidin-1-ylmethylpyrrolidine-1 - carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluoro- phenyl) -ethoxy] pyridin-3-yl} -prop2-inyl) -amide 0.067 11 (300 MHz, CDCb) δ 9.05 (br, 1H), 7.70 (s, 1H), 7.05 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H ), 5.01 (s, 2H), 4.15 (dd, 2H), 3.75 (m, 2H), 3.25 (m, 1H), 2.75 (m, 3H), 2.45 (m, 3H), 2.05 (m, 1H), 1.78 (d, 3H), 1.65 (br, 7H), 534 [M + 1] I- 413 Λ ^σ φΧΦ 4-methylpiperazine-1-carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -amide 0.056 11 (300 MHz, CDCb) δ 7.75 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.75 (s, 1H), 6.02 (q, 1H ), 5.01 (s, 2H), 4.20 (d, 2H), 3.45 (m, 4H), 2.45 (m, 4H), 2.25 (s, 3H), 1.81 (d, 3H), 480 [M + 1] I- 414 ίΥ ^σ ° φ 4-pyrrolidin1 -yl-piperidine-1 carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -amide 0.058 11 (300 MHz, CDCb) δ 7.75 (s, 1H), 7.30 (m, 2H), 7.10 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H ), 5.01 (s, 2H), 4.20 (d, 2H), 3.89 (d, 1H), 2.89 (t, 2H), 2.55 (s, 4H), 2.21 (m, 2H), 1.90 (d, 2H), 1.81 (d, 3H), 1.45 (m, 2H) , 1.25 (m, 2H), 534 [M + 1] I- 415 χά 1 ⁰ 0 (3R, 5S) 3,5-dimethylpiperazine-1-carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -amide 0.063 11 (300 MHz, CDCb) δ 7.75 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.75 (s, 1H), 6.02 (q, 1H ), 5.01 (s, 2H), 4.78 (s, 1H), 4.20 (d, 2H), 3.85 (d, 1H), 2.85 (m, 4H), 2.45 (t, 1H), 1.89 (s, 3H), 1.01 (d, 6H), 494 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 416 Aa ΙΧβ Π ⁰ i yS ^NH > F 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -prop- 2- inyl) -3- (1-methylpiperidin-4-yl) - urea 0.051 11 (300 MHz, CDCb) δ 7.75 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H ), 5.25 (m, 1H), 5.05 (s, 2H), 4.80 (d, 1H), 4.15 (d, 2H), 2.75 (d, 2H), 2.20 (s, 3H), 2.10 (t, 2H), 1.95 (d, 2H), 1.75 (d, 3H), 1.45 (d, 2H), 494 [M + 1] I- 417 Λ çêr 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -prop2-lnll) -3- (3pyrrolidin-1 -IIpropyl) - urea 0.062 11 (300 MHz, CDCb) δ 7.70 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H ), 5.30 (m, 1H), 5.01 (s, 2H), 4.15 (d, 2H), 3.25 (m, 2H), 2.50 (m, 6H), 1.80 (d, 3H), 1.82 (m, 4H), 1.60 (m, 2H), 508 [M + 1] I- 418 à ^u o F 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -prop- 2-lnll) -3- (2pyrrolidin-1 -IIpropyl) -urea 0.052 11 (300 MHz, CDCb) δ 7.70 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.70 (s, 1H), 5.00 (q, 1H ), 5.45 (s, 1H), 5.15 (s, 2H), 4.15 (d, 2H), 3.25 (m, 2H), 2.60 (t, 2H), 2.50 (m, 4H), 1.80 (d, 3H), 1.70 (s, 4H), 496 [M + 1] I- 419 To M ( 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -prop- 2-lnll) -3- (2morfolin-4-yl-ethyl) urea 0.055 11 (300 MHz, CDCb) δ 7.73 (s, 1H), 7.28 (m, 2H), 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H ), 5.25 (s, 1H) 5.15 (s, 2H), 4.15 (d, 2H), 3.65 (m, 4H), 3.25 (m, 2H), 2.45 (m, 6H), 1.80 (d, 3H), 510 [M + 1] I- 420 F 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -prop2-lnll) -3- (3morfolin-4-ylpropyl) - urea 0.064 11 (300 MHz, CDCb) δ 7.70 (s, 1H), 7.30 (m, 2H), 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H ), 5.10 (s, 2H), 4.15 (d, 2H), 3.70 (m, 6H), 3.20 (s, 2H), 2.50 (m, 4H), 1.80 (d, 3H), 1.65 (m, 2H), 524 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 421 u F (R) -2-pyrrolidine-1-ylmethyl-pyrrolidine1-carboxylic acid (3 {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-inyl) - amide 0.071 11 (300 MHz, CDCb) δ 9.05 (br, 1H), 7.70 (s, 1H), 7.05 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H ), 5.01 (s, 2H), 4.15 (dd, 2H), 3.75 (m, 2H), 3.25 (m, 1H), 2.75 (m, 3H), 2.45 (m, 3H), 2.05 (m, 1H), 1.78 (d, 3H), 1.65 (br, 7H), 534 [M + 1] I- 422 IA _ci 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5- (3dimethylaminoprop-1 -inyl) pyridin-2-ylamine 0.071 11 382 [M + 1] I- 423 NH, 3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-inyl) -urea 0.062 11 397 [M + 1] I- 424 Λό N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2-piperidin1-yl-acetamide 0.016 12 (300 MHz, CDCb) δ 7.74 (s, 1H), 7.45 (bm, 1H), 7.31 (dd, IH), 7.07 (t, 1H), 6.73 (s, 1H), 6.00 (q, 1H), 4.99 (s, 2H), 4.26 (d, 2H), 2.98 (s, 2H) , 2.46 (m, 4H), 1.81 (d, 3H), 1.59 (m, 4H), 1.45 (m, 2H), 579 [M + 1] I- 425 Λ ~ ο ά / c N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2-morpholin4-yl-acetamide 0.27 12 (300 MHz, CDCb) δ 7.74 (s, 1H), 7.45 (bm 1H), 7.31 (m, 2H), 7.08 (t, 1H), 6.71 (s, 1H), 6.00 (q, 1H), 5.02 (s, 2H), 4.27 (d, 2H), 3.73 (m, 4H), 3.05 (s, 2H), 2.54 (m, 4H), 1.81 (d, 3H), 481 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 426 rro N- (4- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2-pyrrolidin1-yl-acetamide <0.0009 1 12 (300 MHz, CDCb) δ 7.74 (s, 1H), 7.37 (bm, 1H), 7.31 (dd, 1H), 7.08 (t, 1H), 6.72 (s, 1H), 6.00 (q, 1H), 5.01 (s, 2H), 4.27 (d, 2H), 3.18 (s, 2H), 2.63 (m, 4H), 2.01 (m, 2H), 1.81 (d, 3H), 1.80 (m, 2H), 465 [M + 1] 1- 427 ί ¥ σ ° ψΡ-γ N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2 - ((R) -3hydroxy-pyrrolidin1 -yl-acetamide 0.011 12 (300 MHz, CDCb) δ 7.71 (s, 1H), 7.45 (bm, 1H), 7.31 (dd, 1H), 7.07 (t, 1H), 6.72 (s, 1H), 5.99 (q, 1H), 5.06 (s, 2H), 4.42 (m, 1H), 4.25 (m, 2H), 3.21 (s, 2H), 3, 00 (m, 1H), 2.80 (m, 1H), 2.71 (m, 1H), 2.45 (m, 1H), 2.22 (m, 1H), 1.79 (d, 3H ), 1.78 (m, 2H), 481 [M + 1] 1- 428 'vWf N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2- (4- hydroxy-piperidine- 1-yl) -acetamide 0.012 12 (300 MHz, CDCb) δ 7.73 (d, 1H), 7.38 (bm, 1H), 7.31 (dd, 1H), 7.08 (dd, 1H), 6.72 (d, 1H), 6.00 (q, 1H), 5.03 (s, 2H), 4.26 (d, 2H), 3.74 (m, 1H), 3.02 (s, 2H), 2.78 (m, 2H), 2.32 (m, 2H), 1.92 (m, 4H), 1.80 (d, 3H), 495 [M + 1] 1- 429 rVy i 0 ¹ Pc N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2dimethylaminoacetamide 0.022 12 (300 MHz, CDCb) δ 7.73 (d, 1H), 7.38 (bm, 1H), 7.31 (dd, 1H), 7.08 (dd, 1H), 6.72 (d, 1H), 6.00 (q, 1H), 4.99 (s, 2H), 4.26 (d, 2H), 2.98 (s, 2H), 2.31 (s, 6H), 1.80 (d, 3H), 439 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 430 Αχ N- (3- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-ynyl) -2diethylamino-acetamide 0.013 12 (300 MHz, CDCb) δ 7.73 (d, 1H), 7.59 (bm, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.72 (d, 1H), 6.00 (q, 1H), 4.98 (s, 2H), 4.25 (d, 2H), 3.05 (s, 2H), 2.57 (dd, 4H), 1.80 (d, 3H), 1.03 (t, 6H) 467 [M + 1] 1- 431 rVn | ⁰ Gy XA-Ç kA _to NH, 2- (4-acetylpiperazin-1-yl) -N (3- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -prop2-inyl) -2acetamide 0.027 12 (300 MHz, CDCb) δ 7.73 (d, 1H), 7.31 (dd, 1H), 7.25 (bm, 1H), 7.08 (dd, 1H), 6.71 (d, 1H), 6.00 (q, 1H), 5.04 (s, 2H), 4.27 (d, 2H), 3.66 (m, 2H), 3.52 (m, 2H), 3.08 (s, 2H), 2.78 (m, 2H), 2.32 (m, 2H), 2.53 (m, 4H), 2.10 (s, 3H), 1.81 (d, 3H), 522 [M + 1] I- 432 υφΟ ' 1st shah 4-methylpiperazine-1-carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) -amide Hi 0.61 13 as in example I- 412 (300 MHz, CDCb) δ 7.73 (d, 1H), 7.30 (dd, 1H), 7.07 (t, 1H), 6.78 (d, 1H), 6.01 (q, 1H ), 5.01 (s, 2H), 4.64 (s, 1H), 3.38 (m, 4H), 2.42 (m, 4H), 2.31 (s, 3H), 1.79 (d, 3H), 1.70 (s, 6H), 508 [M + 1] I- 433 (3R, 5S) 3,5-dimethyl-piperazin-1-carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop -2inyl) -amide Hi 1.5 11 (300 MHz, CDCb) δ 7.74 (s, 1 H), 7.30 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1H), 4.93 (s, 2H), 4.59 (s, 1H), 3.75 (m, 2H), 2.82 (m, 2H), 2.35 (m, 2H), 1.80 (d, 3H), 1.71 (s, 6H), 1.09 (d, 6H), 522 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 434 Yr xw (R) -2pyrrolidin-1-ylmethylpyrrolidine-1 carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluoro- phenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) -amide Hi 1.22 11 (300 MHz, CDCb) δ 8.44 (bs, 1H), 7.72 (d, 1H), 7.30 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1H), 4.87 (s, 2H), 3.75 (m, 1H), 3.25 (m , 1H), 2.68 (m, 2H), 2.56 (m, 2H), 2.40 (m, 1H), 2.05 (m, 1H), 1.82 - 1.68 (m, 17H), 1.56 (m, 1H), 562 [M + 1] 1- 435 (S) -2pyrrolidin-1-ylmethylpyrrolidine-1 carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluoro- phenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) -amide Hi 1.58 11 (300 MHz, CDCb) δ 8.44 (bs, 1H), 7.72 (s, 1H), 7.30 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1H), 4.87 (s, 2H), 3.75 (m, 1H), 3.25 (m , 1H), 2.68 (m, 2H), 2.56 (m, 2H), 2.40 (m, 1H), 2.05 (m, 1H), 1.82 - 1.68 (m, 17H), 1.56 (m, 1H), 562 [M + 1] 1- 436 ^NH a 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) -3- (2-morpholin -4-yl-ethyl) -urea Hi 1.11 11 (300 MHz, CDCb) δ 7.72 (s, 1H), 7.31 (dd, 1H), 7.08 (t, 1H), 6.75 (s, 1H), 6.01 (q, 1H ), 5.53 (bm, 1H), 5.00 (s, 2H), 4.66 (bs, 1H), 3.56 (m, 4H), 3.32 (m, 2H), 2.45 (m, 2H), 2.35 (m, 4H), 1.81 (d, 3H), 1.64 (s, 6H), 538 [M + 1] 1- 437 XX _O JÇ1 kA NH, 1- (3- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) -3- (2-pyrrolidin -1 -yl-ethyl) -urea Hi 0.61 11 (300 MHz, CDCb) δ 7.72 (s, 1H), 7.31 (dd, 1H), 7.08 (t, 1H), 6.77 (s, 1H), 6.01 (q, 1H ), 5.68 (bm, 1H), 5.14 (bs, 1H), 5.01 (s, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.50 (m , 4H), 1.81 (d, 3H), 1.68 (m, 4H), 1.63 (s, 6H), 522 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 438 NH, F 4-pyrrolidin1 -yl-piperidine-1 carboxylic acid (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -1,1dimethyl-prop-2inyl) - amide Hi 0.72 11 (300 MHz, CDCb) δ 7.73 (s, 1H), 7.31 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1H ), 5.68 (bm, 1H), 4.95 (s, 2H), 4.68 (bs, 1H), 3.88 (m, 2H), 2.82 (m, 2H), 2.58 (m, 4H), 2.28 (m, 1H), 1.92 (m, 2H), 1.81 (d, 3H), 1.80 (m, 4H), 1.70 (s, 6H) , 1.50 (m, 2H), 562 [M + 1] 1- 439 ^WH > cyclohexylamide (3- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} propinoic acid Hi 0.46 11 (300 MHz, CDCb) δ 7.85 (d, 1H), 7.31 (dd, 1H), 7.09 (t, 1H), 6.78 (d, 1H), 6.00 (q, 1H ), 5.69 (bd, 1H), 5.14 (s, 2H), 4.12 (m, 1H), 1.81 ds, 3H), 1.20 (d, 6H) 410 [M + 1] 1- 440 w NH, isopropylamide (3- {6-amino5- [1- (2,6-dichloro3-fluoro-phenyl) ethoxy] -pyridin-3-yl} propinoic acid Hi 0.43 11 (300 MHz, CDCb) δ 7.86 (s, 1H), 7.31 (dd, 1H), 7.09 (t, 1H), 6.79 (s, 1H), 6.00 (q, 1H ), 5.72 (bd, 1H), 5.14 (s, 2H), 3.82 (m, 1H), 1.95 (m, 2H), 1.80 (d, 3H), 1.72 (m, 2H), 1.65 (m, 2H), 1.38 (m, 2H), 1.20 (m, 2H), 450 [M + 1] 1- 441 V.NH, u VA. ^NH > 4- (3-amino-3methyl-but-1-yl) -2 [1- (2,6-dichloro-3floro-phenyl) -ethoxy] phenylamine Hi 1.06 11 (300 MHz, CDsOD) δ 7.60 (d, 1H), 7.45 (dd, 1H), 7.25 (t, 1H), 6.66 (d, 1H), 6.06 (q, 1H ), 1.84 (d, 3H), 1.66 (s, 6H), 382 [M + 1] I- 442 ίΎ ^ ο L TF ^f (4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-methyl-piperazin1-yl) -methanone 16% a 1 one 13 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.51 (m, 1H), 7.40 (m, 5H), 7.10 (m, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.94 (s, 2H), 3.58 (m, 4H), 2.53 (m, 4H), 2.32 (s, 3H), 1.84 (d, 3H), 503 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 443 Çcjxi (4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-pyrrolidin-1 -IIpiperidin-1 -II) methanone 13% a 1 one 13 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.54 (m, 1H), 7.32 (d, 5H), 7.17 (m, 1H), 6.90 (d, 1H ), 5.79 (q, 1H), 4.93 (s, 2H), 4.60 (m, 1H), 3.80 (m, 1H), 2.95 (m, 2H), 2.64 (m, 4H), 2.34 (m, 1H), 1.95 (m, 2H), 1.81 (m, 4H), 1.73 (d, 3H), 1.56 (m, 2H), 557 [M + 1] 1- 444 (4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) ((3R, 5S) -3,5dimethyl-piperazin1-yl) -methanone 10% a 1 one 13 (300 MHz, CDCb) δ 7.9 (d, 1H), 7.50 (m, 1H), 7.36 (m, 5H), 7.11 (m, 1H), 6.90 (s, 1H), 5.81 (q, 1H), 4.93 (s, 2H), 4.62 (m, 1H), 3.66 (m, 1H), 2.85 (m, 2H), 2.65 (m, 1H), 2.40 (m, 1H), 1.73 (d, 3H), 1.10 (m, 7H), 517 [M + 1] 1- 445 % Γ ^% Α ° ^χ τ ^Ν (4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) ((S) -2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl) -methanone 15% a 1 one 13 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.73 (m, 1H), 7.53 (m, 3H), 7.34 (d, 2H), 7.13 (m, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.93 (s, 2H), 4.45 (m, 1H), 3.50 (m, 2H), 2.70 (m, 4H ), 1.73 (d, 3H), 1.20-2.0 (m, 10H), 557 [M + 1] 1- 446 [Ay AV ⁿ (4- {6-amino-5- [1 (3-fluoro-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) ((R) -2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl) -methanone 12% a 1 one 13 (300 MHz, CDCb) δ 7.90 (s, 1H), 7.73 (m, 1H), 7.53 (m, 3H), 7.34 (d, 2H), 7.13 (m, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.93 (s, 2H), 4.45 (m, 1H), 3.50 (m, 2H), 2.70 (m, 4H ), 1.73 (d, 3H), 1.20-2.0 (m, 10H), 557 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 449 O ^ NH 0 JL JLJ UO * ^laughs ' FF ** (4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -phenyl) N- (1 - methylpiperidin-4-yl) benzamide 12% a 1 one 13 (300 MHz, CDCb) δ 7.90 (d, IH), 7.75 (d, 2H), 7.72 (m, 1H), 7.52 (m, 1H), 7.48 (d, 2H), 7.10 (m, 1H), 6.89 (d, 1H), 6.00 (bd, 1H), 5.80 (q, 1H), 4.93 (s, 2H), 4.02 (m, 1H), 2.85 (m, 2H), 2.31 (s, 3H), 2.16 (m, 2H), 2.05 (m, 2H), 1.73 (d, 3H), 1.62 (m, 2H), 517 [M + 1] 1- 450 Y-o T ^ F 4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -N- (2pyrrolidin-1-yl-ethyl) benzamide 7% a 1uM at 13 (300 MHz, CDCb) δ 7.90 (d, 1H), 7.79 (d, 2H), 7.55 (m, 2H), 7.48 (d, 2H), 7.13 (m, 1H), 7.08 (bs, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.94 (s, 2H) , 3.58 (m, 2H), 2.78 (m, 2H), 2.62 (m, 4H), 1.81 (m, 4H), 1.72 (d, 3H), 517 [M + 1] 1- 451 XfA ^ ^p NH, 4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -N- (2morpholin-4-yl-ethyl) benzamide 12% a 1 one 13 (300 MHz, CDCb) δ 7.91 (d, 1H), 7.78 (d, 2H), 7.51 (m, 2H), 7.39 (d, 2H), 7.10 (m, 1H), 6.91 (d, 1H), 6.76 (bs, 1H), 5.82 (q, 1H), 4.97 (s, 2H), 3.72 (m, 4H), 3.57 (m, 2H ), 2.62 (m, 2H), 2.52 (m, 4H), 1.73 (d, 3H), 533 [M + 1] I- 452 9> '- · 4- {6-amino-5- [1 (3-fluor-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -N- (3pyrrolidin-1 -IIpropyl) -benzamide 3% a 1 one 13 (300 MHz, CDCb) δ 8.81 (s, 1H), 7.92 (s, 1H), 7.78 (d, 2H), 7.53 (m, 1H), 7.48 (d, 2H), 7.13 (m, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.90 (s, 2H), 3.60 (m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.85 (m, 6H), 1.73 (d, 3H), 531 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 453 T fAV t « ₂ FF ^ 4> - {6-amino-5- [1 (3-fluoro-2trifluoromethylphenyl) -ethoxy] pyridin-3-yl} -N- (3morpholin-4-ylpropyl) -benzamide 10% a 1 one 13 (300 MHz, CDCb) δ 7.93 (s, 1H), 7.80 (d, 2H), 7.53 (m, 3H), 7.38 (d, 2H), 7.10 (m, 1H), 6.91 (d, 1H), 5.82 (q, 1H), 4.95 (s, 2H), 3.70 (m, 4H), 3.57 (m, 2H), 2.54 (m, 6H), 1.81 (m, 2H), 1.73 (d, 3H), 547 [M + 1] 1- 454 F 6-amino-5- [1 (2,6.dichloro-3 fluoro-phenyl) -ethoxy] nicotinonitrile 7% a 1 one Example I- 454 (400 MHz, DMSO- de) δ7.93 (s, 1H), 7.56 (m, 1H), 7.46 (t, 1H), 6.88 (br, 2H), 6.76 (s, 1H), 6.02 (q, 1H), 1.77 (d, 3H), 325 [M-1] 1- 455 THE 6-amino-5- [1- (2,6.dichloro-3-cyano-phenyl) -ethoxy] nicotinonitrile 6% a 1 one Example I- 455 (400 MHz, DMSO- de) δ 8.00 (s, 1H), 7.81 (d, 1H), 7.07 (t, 2H), 5.78 (d, 1H), 1.74 (d, 3H), 332 [M-1] 1- 456 .nh ₂ F 5-aminomethyl-3 [1- (2,6.dichloro-3fluor-phenyl) -ethoxy] pyridin-2-ylamine 0% a 1 one Example I- 456 (400 MHz, DMSO- de) δ 7.53 (m, 1H), 7.43 (m, 2H), 6.76 (s, 1H), 5.98 (q, 1H), 5.47 (br , 2H), 1.74 (d, 3H) 331 [M + 1] 1- 457 X F (R) -2pyrrolidin-1-ylmethylpyrrolidine-1 carboxylic acid {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-ylmethyl} amide 1% a 1 one Example I- 457 (400 MHz, DMSO- de) δ 9.58 (s, 1H), 7.93 (s, 1H), 7.55 (m, 1H), 7.40 (s, 1H), 6.59 (dd , 1H), 6.80 (d, 1H), 6.06 (t, 1H), 4.19 (dd, 1H), 4.10 (dd, 1H), 3.94 (dd, 1H), 3.85 (dd, 1H), 3.21 (m, 2H), 3.15 (m, 2H), 3.01 (m, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.84 (m, 2H), 1.78 (d , 3H) 1.72 (br, 1H), 511 [M + 1] 1- 458 nCo A? F N- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-ylmethyl} methanesulfonamide 0% a 1 one As in Example I- 13 (400 MHz, DMSO- de) δ 7.51 (m, 1H), 7.43 (t, 2H), 7.28 (m, 1H), 6.70 (s, 1H), 5.96 (q, 1H), 5.68 (s, 2H), 3.84 (d, 2H), 2.68 (s, 3H), 1.76 (d, 3H) 409 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 459 _ »NH N- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-ylmethyl} acetamide 2% a 1 one As in Example I- 14 (400 MHz, CDCb): d 7.49 (s, 1H), 7.29 (m, 1H), 7.06 (t, 1H), 6.71 (s, 1H), 6.03 (q, 1H), 5.49 (bs, 1H), 4.82 (bs, 2H) 4.29 (dd, 1H), 4.12 (dd, 1H), 1.96 (s, 3H), 1.83 (d, J 8.0 Hz, 3H), 372 [M + 1] 1- 460 μ A ΑΛΑγ » Çs. *> F N- {6-amino-5- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-ylmethyl} -4methylbenzenesulfonamide 9% a 1 one As in Example I- 13 (400 MHz, CDCb): d 7.69 (d, 2H), 7.29 (m, 4H), 7.06 (t, 1H), 6.69 (s, 1H), 5.98 (q, 1H), 4.84 (bs, 2H), 4.51 (m, 1H), 3.86 (dt, 2H), 2.43 (s, 3H), 1.83 (d, J 8.0 Hz, 3H), 485 [M + 1] 1- 461 F 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5-vinylpyridin-2-ylamine Hi 0.68 3 (400 MHz, CDCb): d 7.56 (s, 1H), 7.29 (m, 1 H), 7.05 (t, 1H), 6.91 (s, 1H), 6.19 (dd , 1H), 6.07 (q, 1H), 5.40 (d, J 16 Hz, 1H) 5.02 (d, J 12 Hz, 1H), 4.85 (bs, 2H), 1.85 (d, J 8.0 Hz, 3H), 327 [M + 1] I- 462 F (S) -1- {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -ethan 1,2-diol 2% a 1 one Example I- 462 (400 MHz, CDCb): d 7.55 (s, 1H), 7.29 (m, 1H), 7.05 (t, 1H), 6.82 (s, 1H), 6.05 (q, 1H), 4.82 (bs, 2H), 4.63 (m, 1H), 3.54 (m, 4H), 1.83 (d, J 8.0 Hz, 3H), 362 [M + 1] I- 463 ^ • 4 (R) -1 - {6-amino-5 [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] pyridin-3-yl} -ethane- 1,2-diol 2% a 1 one Example I- 462 (400 MHz, CDCb): d 7.55 (s, 1H), 7.29 (m, 1H), 7.05 (t, 1H), 6.82 (s, 1H), 6.05 (q, 1H), 4.82 (bs, 2H), 4.63 (m, 1H), 3.54 (m, 4H), 1.83 (d, J 8.0 Hz, 3H), 362 [M + 1] I- 464 όΦ ° ^ ^Η NH, 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5- [1 Hpirazol-4-yl) pyridin-2-ylamine Hi 0.10 3 (400 MHz, CDCb): d 7.65 (s, 2H), 7.52 (s, 1H), 7.37 (m, 1H), 7.13 (m, 1H), 7.04 (s, 1H), 6.17 (q, J 8.0 Hz, 1H), 1.93 (d, J 8.0 Hz, 3H) 367 [M + 1]

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 465 F 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5- [1- (2pyrrolidin-1-yl-ethyl) - 1 H-pyrazol-4-yl] pyridin-2-ylamine Hi 0.34 14 (400 MHz, CDCb): d 7.71 (s, 1H), 7.55 (s, 2H), 7.37 (m, 1H), 7.06 (m, 1H), 6.87 (s, 1H), 6.09 (m, 1H), 4.26 (t, J 8.0 Hz, 2H), 2.96 (t, J 8.0 Hz, 2H), 2.55 (m, 4H), 1.87 (d, J 8.0 Hz, 3H), 1.26 (m, 4H) 465 [M + 1] 1- 466 Λ A? F 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5- [1- (2diisopropylaminoethyl) -1 H-pyrazol-4yl] -pyridin-2ylamine Hi 0.47 14 (400 MHz, CDCb): d 7.76 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.86 (m, 1H), 6.08 (m, 1H), 4.05 (t, J 8.0 Hz, 2H), 2.83 (t, 2H), 1.86 (d , J 4.0 Hz, 3H), 0.96 (d, J 8.0 Hz, 12H) 495 [M + 1] 1- 467 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -5- [1- (2morfolin-4-yl] pyridin-2-ylamine Hi 0.083 14 (400 MHz, CDCb): d 7.72 (s, 1H), 7.60 (s, 1H), 7.50 (s, IH), 7.38 (m, 1H), 7.13 (m, 1H), 7.05 (s, 1H), 6.19 (m, 1H) 4.61 (m, 2H), 3.89 (m, 4H), 3.53 (m, 2H), 3.02 (m, 4H), 1.93 (d, J 8.0 Hz, 3H), 481 [M + 1] 1- 468 Γη ^ΝΗ * F 1 5-bromo-3- (3-fluoro-2-methoxybenciloxy) -pyridin2-ylamine 8% a 1 one 15 (400 MHz, DMSO- de) δ 7.67 (s, 1H), 7.43 (d, 1H), 7.40 (d, 1H), 7.33 (t, 1H), 7.20 (m, 1H), 6.00 (s, 2H) 5.19 (s, 2H), 3.96 (s, 3H) 328 [M + 1] 1- 469 aX NH, 5-bromo-3- [1- (3-fluoro-2-methoxyphenyl) -ethoxy] - pyridin-2-ylamine 7% a 1 one 15 (400 MHz, DMSO- de) δ 7.51 (s, 1H), 7.25 (d, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6.94 (s, 1H), 6.02 (s, 2H), 5.72 (q, 1H), 3.93 (s, 3H), 1.57 (d, 3H) 342 [M + 1]

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 470 T yS {4- [6-amino-5- (3-fluoro-2-methoxybenciloxy) -pyridin3-yl] -phenyl} ((3R, 5S) -3,5dimethyl-piperazin1-yl) -methanone 3% a 1 one 3 (400 MHz, DMSO- de) δ 9.24 (s, 1H), 8.61 (d, 1H), 7.96 (d, 1H), 7.81 (d, 2H), 7.57 (d, 1H), 7.43 (d, 2H), 7.32 (t, 1H), 7.18 (m, 1H), 5.34 (s, 2H), 3.91 (s, 3H), 3.39 (m, 2H), 2.49 (m, 4H), 1.21 (m, 6H), 465 [M + 1] 1- 471 0 i A (4- {6-amino-5- [1 (3-fluor-2-methoxyphenyl) -ethoxy] pyridin-3-yl] -phenyl} ((3R, 5S) -3,5dimethyl-piperazin1-yl) -methanone 1% a 1 one 3 (400 MHz, DMSO- de) δ 9.25 (d, 1H), 8.64 (d, 1H), 7.88 (s, 1H), 7.61 (d, 2H), 7.53 (d , 2H), 7.46 (s, 1H), 7.35 (d, 1H), 7.21 (t, 1H), 7.13 (m, 1H), 6.03 (m, 1H), 3 , 93 (s, 3H), 3.38 (m, 2H), 2.49 (m, 4H), 1.67 (d, 3H), 1.20 (m, 6H) 479 [M + 1] I- 472 Br Yil N ^ ° i ^{N NHj} F 5-bromo-3- (3-fluoro-2-isopropoxybenciloxy) -pyridin2-ylamine Hi 12.1 15 (400 MHz, DMSO- de) δ 7.59 (s, 1H), 7.36 (d, 1H), 7.31 (d, 1H), 7.25 (t, 1H), 7.12 (m , 1H) 5.90 (s, 2H), 5.10 (s, 2H), 4.43 (m, 1H), 1.26 (d, 6H) 356 I- 473 the fill rf ^ Y ^ o -γ · ^Μ {4- [6-amino-5- (3-fluoro-2-isopropoxybenciloxy) -pyridin- 3-yl] -phenyl} ((3R, 5S) -3,5dimethyl-piperazin1-yl) -methanone Hi 12.7 3 (400 MHz, DMSO- de) δ 9.45 (d, 1H), 8.79 (q, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.80 (d, 2H), 7.58 (d, 2H), 7.41 (d, 1H), 7.32 (t, 1H), 7.17 (m, 1H), 5.37 (s, 2H), 4.45 (m, 1H), 3.40 (m, 2H), 2.49 (m, 4H), 1.28 (d, 8H), 1.20 (m, 6H) 493 I- 474 Τ '? i ô ⁰ i ' ^N F 5- (4-amino-phenyl- 3- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] -pyridin-2ylamine 3 (400 MHz, DMSO- de) δ 7.66 (d, 1 H), 7.55 (q, 1 H), 7.43 (t, 1H), 7.02 (d, 2H), 6.81 (s, 1H), 6.56 (d, 2H), 6.08 (q, 1H), 5.60 (s, 2H), 5.08 (s, 2H), 1.78 (d, 3H) 393

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 475 To HUN, Ah, methyl ester del acido (4- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} - phenoxy) -acetic Hi 0.20 As in Example I- 55 (400 MHz, CDCb): d 7.82 (s, 1H), 7.30 (m, 3H), 7.06 (m, 1H), 6.95 (m, 3H), 6.12 (q, 1H), 480 (m, 2H), 4.66 (s, 2H), 3.82 (s, 3H), 1.86 (d, J 8.0 Hz, 3H), 467 1- 476 F (4- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} - phenoxy) -acetic acid Hi 0.20 As in Example I- 55 (400 MHz, CDCb): d 7.70 (s, 1H), 7.50 (m, 2H), 7.45 (m, 2H), 7.20 (m, 2H), 6.85 (m, 2H), 6.05 (q, 1H), 5.72 (s, 2H), 4.49 (s, 2H), 3.82 (s, 3H), 1.75 (d, J 8.0 Hz, 3H), 453 1- 477 2- (4- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} - phenoxy) -1 - ((3R, 5S) 3,5- dimethylpiperazin-1 -II) ethanone Hi 0.027 4 (400 MHz, CDCb): d 7.48 (s, 1H), 7.35 (m, 1H), 7.20 (m, 2H), 7.12 (m, 2H), 7.01 (m, 2H), 6.20 (q, 1H), 4.73 (m, 3H), 4.10 (m, 1H), 3.36 (m, 1H), 3.13 (m, 2H), 2, 84 (m, 1H), 1.94 (d, J 8.0 Hz, 3H), 1.34 (m, 6H), 548 1- 478 F 2- (4- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} - phenom- xi) -1 - ((R) -3hydroxy-pyrrolidin1-yl) -ethanone Hi 0.041 4 (400 MHz, CDCb): d 7.48 (s, 1H), 7.36 (m, 1 H), 7.21 (d, 2H), 7.19 (m, 2H), 7.10 (m, 2H), 7.01 (m, 2H), 6.20 (q, 1H), 4.65 (m, 2H), 4.55 (m, 1H), 3.69 (m, 3H), 3.48 (m, 1H), 2.10 (m, 3H), 1.92 (m, 5H), 521 1- 479 f 4- [2- (4- {6 amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3-yl} -phenoxy) -acetyl] piperazine-1-carboxylic acid terbutil ester Hi 0.16 4 (400 MHz, CDCb): d 7.50 (s, 1H), 7.36 (m, 1H), 7.22 (d, 2H), 7.19 (m, 2H), 7.15 (m, 2H), 7.00 (m, 2H), 6.20 (q, 1H), 4.75 (s, 2H), 3.57 (m, 4H), 3.45 (m, 4H), 1, 93 (d, J 8.0 Hz, 3H), 1.47 (s, 9H) 620

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 480 2- (4- {6-amino-5 [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} - phenoxy) -1 - ((R) -2pyrrolidin-1-ylmethylpyrrolidin -1 -II) ethanone 4 (400 MHz, CDCb): d 7.48 (s, 1H), 7.36 (m, 1H), 7.20 (d, 2H), 7.15 (m, 2H), 7.00 (d, 2H), 6.20 (q, 1H), 4.68 (s, 2H), 4.46 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3, 60 (m, 1H), 3.52 (m, 1H), 3.50 (m, 1H), 3.12 (m, 1H), 3.09 (m, 1H), 2.83 (m, 1H ), 1.93 (d, J 8.0 Hz, 3H), 2,161.66 (m, 10H), 588 1- 481 p, 4 F 5-bromo-3- (3-fluoro-6, 7, 8, 9tetrahydro-5Hbenzocycloheptane-5-yloxy) -pyridin2-ylamine 15 (400 MHz, DMSO- de) δ 7.57 (d, 1H), 7.16 (m, 3H), 6.95 (dt, 1H), 6.07 (d, 2H), 5.63 (d, 1H), 2.10 (m, 2H), 2.16 (m, 2H), 1.86 (m, 1H), 1.77 (m, 2H), 1.34 (m, 1H), 352 I- 482 the 3rd: NH, {4- [6-amino-5- (3-fluoro-6, 7, 8, 9tetrahydro-5Hbenzocycloheptane-5-yloxy) -pyridin 3-yl] -phenyl} ((3R, 5S) -3,5dimethyl-piperazin1-yl ) -methanone 3 493 I- 483 0 % \ H 3- (3-fluoro-6, 7, 8, 9-tetrahydro-5Hbenzocycloheptane-5-yloxy) -5- [4- (2pyrrolidin-1 -IIetoxy) -phenyl-pyridin2-ylamine 3 462 I- 484 hJLh, J. V / ^NHj F N- {4- [6-amino-5 (3-fluoro- 6, 7, 8, 9tetrahydro-5Hbenzocycloheptane-5-yloxy) -pyridin3-yl] -phenyl} methanesulfonamide 3 442

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 485 cx jO F 3- (3-fluoro-6, 7, 8, 9-tetrahydro-5Hbenzocycloheptane-5-yloxy) -5- (1 Hpirazol-4-yl) pyridin-2-ylamine 3 337 [M-1] 1- 486 çX F 5-bromo-3- [1- (2chloro-3-fluorophenyl) -ethoxy] pyridin-2-ylamine 0% at 1 one 15 (400 MHz, CDCb): d 7.68 (s, 1H), 7.24 (m, 3H), 6.69 (s, 1H), 5.64 (q, 1H), 4.78 (bs, 2H), 1.68 (d, J 8.0 Hz, 3H), 347 1- 487 F 3- [1- (2-chloro-3-fluoro-phenyl) -ethoxy] 5- [4- (2-pyrrolidin1 -yl-ethoxy) -phenyl] pyridin-2-ylamine Hi 3.30 3 (400 MHz, CDCb): d 7.50 (s, 1H), 7.30 (m, 2H), 7.20 (m, 3H), 7.00 (s, 1H), 6.95 (m, 2H), 5.90 (q, 1H), 4.36 (m, 2H), 3.85 (m, 2H), 3.55 (m, 2H) , 2.95 (m, 2H), 2.10 (m, 4H), 1.82 (d, J 8.0 Hz, 3H), 456 1- 488 CjiN cr ° x 5’-benciloxy [2,3 ’] bipyridinyl-6’ylamine > 20 16 (CDCb) d 5.15 (brs, 2H), 5.19 (s, 2H), 7.17 (m, 1H), 7.34-7.46 (m, 5H), 7.64 (d, J = 8 Hz, 1H), 7.70 (td, J = 7.8, 1.9 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 2 Hz, 1H), 8.63 (d, J = 4 Hz, 1H), 278 1- 489 O JL * i P ⁶ P '°' T NHj 5-benciloxy [3,3 '] bipyridinyl-6'ylamine > 20 16 (CDCb) d 5.17 (s, 2H), 5.27 (brs, 2H), 7.19 (d, J = 2 Hz, 1H), 7.33 (dd, J = 7.8, 4.6 Hz, 1H), 7.35-7.44 (m, 5H), 7.70 (dt, J = 2.8 Hz, 1H), 7.85 (d, J = 2 Hz, 1H), 8.56 (dd, J = 1.6, 4.8 Hz, 1H), 8.71 (d, J = 2 Hz, 1H), 278 1- 490 n ^ n fV ⁰ : NHj 3-benciloxy-5pyrimidin-5-ylpyridin-2-ylamine > 20 16 (CDCb) d 5.22 (s, 2H), 6.15 (brs, 2H), 7.21 (s, 1H), 7.43 (m, 5H), 7.77 (s, 1H), 8 , 81 (s, 2H), 9.20 (s, 1H), 279

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 491 5-benciloxy [3.3 ’] bipyridinyl6’, 6-diamine > 20 16 (CDCb) d 4.40 (br s, 2H), 4.94 (brs, 2H), 5.13 (s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1 H), 7.35- 7.44 (m, 5H), 7.56 (dd, J 2.4, 8.4 Hz, 1H), 7.77 (d, J 1.6 Hz, 1H), 8.13 (d, J = 2 Hz, 1H), 293 I- 492 Cl A] (j * ⁰ i ^N NH, 5 ’- (2-chlorobenciloxy) [2,3’] bipyridinyl-6’ilamine 8.24 16 (CDCb) d 5.33 (s, 2H), 5.99 (bs, 2H), 7.22- 7.26 (m, 1H), 7.29- 7.37 (m, 2H), 7.42- 7.51 (m, 2H), 7.63 (d, 1H), 7.72 (dt, 1H), 7.99 (d, 1H), 8.13 (d, 1H), 8.65 (dd, 1H), 312 I- 493 CI rA U ⁰ k 5- (2-chlorobenciloxy) [3,3 ’] bipyridinyl-6’ylamine 4.6 16 312 I- 494 φ 3- (2-chlorobenciloxy) -5-pyrimidin-5-yl-pyridin2-ylamine 19.3 16 313 I- 495 Ϊ ò Γί ⁰ t 5- (chlorobenciloxy) [3.3 ’] bipyridinyl6’, 6-diamine 4.31 16 317 I- 496 UX _C | XX NH ₂ 5 ’- (4-chlorobenciloxy) [2,3’] bipyridinyl-6’ylamine 14 16 (CDCI3) d 5.18 (s, 2H), 5.48 (bs, 2H), 7.19- 7.22 (m, 1H), 7.38 (s, 4H), 7.63 - 7.65 (m, 1H), 7.73 (dt, 1H), 7.89 (d, 1H), 8.17 (d, 1H), 8.63 (d, 1H), 312 I- 497 The lp] ⁰ _α Λ ^> NH, 5- (4-chlorobenciloxy) [3.3 ’] bipyridinyl-6ylamine 14.1 16 312 I- 498 Çy Η. 3- (4-chlorobenciloxy) -5pyrimidin-5-ylpyridin-2-ylamine > 20.0 16 313

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 499 NHj ll ^ j ⁰ T NH, 5- (4-chlorobenciloxy) [3,3 '] bipyridinyl6', 6-diamine > 20.0 16 317 1- 500 Q [ΙΊ ⁰ 1 SA, F 5 ’- (2-chloro-3,6difluoro-benciloxy) [2,3’] bipyridinyl-6’ilamine 1.8 16 (CDCb) δ 5.39 (s, 2H), 6.19 (bs, 2H), 7.08 (dt, 1H), 7.21-7.28 (m, 2H), 7.65 (d, 1H), 7.77 (dt, 1H), 8.13 (d, 1H), 8.67 (dd, 1H) 348 1- 501 Çr NH, 5- (2-chloro-3,6difluoro-benciloxy) [3.3 ’] bipyridinyl-6ylamine 0.282 16 348 I- 502 5- (2-chloro-3,6difluoro-benciloxy) [3,4 ’] bipyridinyl-6ylamine 0.211 16 348 I- 503 Q fUL-o-Q CXp NHj 3- (2-chloro-3,6difluoro-benciloxy) 5-pyrimidin-5-ylpyridin-2-ylamine 2.15 16 349 I- 504 Wi Q NH, 5- (2-chloro-3,6difluoro-benciloxy) - [3.3 ’] bipyridinyl- 6,6’-diamine 0.209 16 363 I- 505 & ·? 5 ’- (2,6-dichlorobenciloxy) [2,3’] bipyridinyl-6’ylamine 2.84 16 (CDCb) d 5.47 (s, 2H), 5.76 (bs, 2H), 7.21- 7.25 (m, 1H), 7.27- 7.32 (m, 1H), 7.37- 7.41 (m, 2H), 7.66 (d, 1H), 7.75 (dt, 1H), 8.06 (d, 1H), 8.17 (d, 1H), 8.66 (dd, 1H), 346 I- 506 Q ΛγΔ • LA _CI ^NH » 5- (2,6-dichlorobenciloxy) [3.3 ’] bipyridinyl-6ylamine 2.71 16 346 I- 507 0 XOV Pi ° ί / Md ^NH > 5- (2,6-dichlorobenciloxy) [3,4 ’] bipyridinyl-6ylamine 1.3 16 346

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Table 2 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 508 ►pM X-JU 3- (2,6-dichlorobenciloxy) -5 pyrimidin-5-yl-pyridin2-ylamine 10.3 16 347 1- 509 NHj Çy 5- (2,6-dichlorobenciloxy) [3,3 ’] bipyridinyl6,6’-diamine 0.578 16 361 ΙδΙΟ íl? 5- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] [3,3 ’] bipyridinyl6,6’-diamine 0.0167 16 (CDCI3) d 1.87 (d, J = 6.6 Hz, 3H), 4.60 (brs, 2H), 4.96 (brs, 2H), 6.11 (q, J = 6.6 Hz, 1H), 6.56 (d, J = 8, 4 Hz, 1H), 6.91 (s, 1H), 7.06 (t, J = 8.5 Hz, 1H), 7.31 (dd, J = 4.8, 8.7 Hz, 1H), 7.48 (dd, J = 1.8, 8.4 Hz, 1H), 7.75 (s, 1H), 8.05 (s, 1H), 393 1- 511 \ s? X _Ç! ^NK Í {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [2,3' 'bipyridinyl-4yl} - (4-methylpiperazin-1 -II) methanone 0.0742 16 (CDCI3) d 1.87 (d, 6.6 Hz, 3H), 2.37 (s, 3H), 2.39 (brs, 2H), 2.56 (brs, 2H), 3.43 (brs , 2H), 3.86 (brs, 2H), 5.13 (brs, 2H), 6.21 (q, J = 6.7 Hz, 1H), 7.04 (dd, J = 8.1, 8.7 Hz, 1H), 7.10 (dd, J = 1.2, 5.1 Hz, 1H), 7.29 (dd, J = 5.1.9.3 Hz, 1H), 7.48 (s, 1H), 7.57 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H) 8.65 (dd, J = 0.6, 4.8Hz, 1H), 504

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 512 , ο ^Λ η t LA _C , NH, {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [2,3' 'bipyridinyl-6yl} - (4-methylpiperazin-1 -II) methanone 0.0629 16 (CDCb) d 1.87 (d, J = 6.6 Hz, 3H), 2.36 (s, 3H), 2.46 (m, 2H), 2.58 (m, 2H), 3.66 (m, 2H), 3.89 (m, 2H) , 5.08 (br s, 2H), 6.17 (q, J = 6.6 Hz, 1H), 7.05 (dd, J = 8.1.8.8 Hz, 1H), 7.31 (dd, J = 5.0, 8.9 Hz, 1H), 7.46 (dd, J = 0.8, 7.7 Hz, 1H), 7.51 (dd, J = 1.8, Hz, 1H), 7.55 (dd, J = 0.8, 0.8 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 504 Ιδη Çl I pAs UÇ NH, {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [3,3' 'bipyridinyl-5yl} - (4-methylpiperazin-1 -II) methanone 0.034 16 (CDCb) d 1.88 (dd = 6.6 Hz, 3H), 2.38 (s, 3H), 2.44 (m, 2H), 2.56 (m, 2H), 3.52 (m , 2H), 3.87 (m, 2H), 5.05 (br s, 2H), 6.12 (q, J = 6.7 Hz, 1H), 6.97 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.1.8.7 Hz, 7.33 (dd, J = 5.0, 8.9 Hz, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.65 d, J = 2.4 Hz, 1H), 504 I- 514 0 0 ' ^f yV ° A ⁿ υχ Ή {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [3,3' 'bipyridinyl-6yl} - (4-methylpiperazin-1 -II) methanone 0.0213 16 (CDCb): d 1.88 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H), 2.52 (brs, 2H), 2.61 (brs, 2H), 3, 74 (brs, 2H), 3.89 (brs, 2H), 5.02 (brs, 2H), 6.12 (q, J = 6.7 Hz, 1H), 6.97 (d, J = 1 , 2 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 7.33 (dd, J = 4.8, 8.7 Hz, 1H), 7.68 (d, J = 9 Hz, 1H), 7.76 (dd, J = 1.8, 8.4 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 8.59 (d, J = 1.5 Hz, 1H), 504

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 515 Xa xA {6'-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] [3,4 '' bipyridinyl-2yl} - (4-methylpiperazin-1 -II) methanone 0.0387 16 (CDCb): d 1.88 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H), 2.51 (m, 2H), 2.61 (m, 2H), 3.67 (m, 2H), 3.90 (m, 2H), 5.08 (br s, 2H), 6.14 (q, J = 6.7 Hz, 1H), 7.05 (s, 1H), 7.06 (d, J = 7.8, 9 Hz, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 5.0, 7.7 Hz, 1H), 7.66 (d, J = 1.2 Hz , 1H), 8.00 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H), 504 I- 516 NH, look Yy ° T NH, 5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] [3,3 ’] bipyridinyl6,6’-diamine 0.0393 16 (CDCb) d 1.83 (d, J = 6.6 Hz, 3H), 4.55 (brs, 2H), 4.87 (brs, 2H), 5.95 (q, J = 6.5 Hz , 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.93-7.12 (m, 3H), 7.48 (dd, J = 1.8, 8.4 Hz, 1H), 7.76 (s, 1H), 8.09 (s, 1H), 377 I- 517 PzN ^ O The ’'Υ ^ τΑο'γ ^' nh, {6'-amino-5 '- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] [2,3' 'bipyridinyl-5yl} - (4-methylpiperazin-1 -II) methanone 0.131 16 (CDCb) d 1.84 (d, J = 6.6 Hz, 3H), 2.39 (s, 3H), 2.53 (brs, 4H), 3.63 (brs, 2H), 3.82 (brs, 2H), 5.09 (brs, 2H), 6.06 (q, J = 6.5 Hz, 1H), 6.93-7.10 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1 H), 7.76 (dd, J = 2.1.8.4 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.66 (d, J = 1.5 Hz, 1H), 488

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 518 Ah, {6'-amino-5 '- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] [2,3' 'bipyridinyl-4yl} - (4-methylpiperazin-1 -II) methanone 0.209 16 (CDCb) d 1.84 (d, J = 6.6 Hz, 3H), 2.40 (s, 3H), 2.45 (brs, 2H), 2.61 (brs, 2H), 3.48 (brs, 2H), 3.89 (brs, 2H), 5.13 (brs, 2H), 8.06 (q, J = 6.6 Hz, 1H), 6.93-7.10 (m, 2H), 7.12 (dd, J = 1.2, 5.1 Hz, 1H), 7.52 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), 8, 24 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H), 488 I- 519 XÔp 'kjXp ^NH 1 {6'-amino-5 '- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] [2,3' 'bipyridinyl-6yl} - (4-methylpiperazin-1 -II) methanone 0.466 16 (CDCb) d 1.84 (d, J = 6.6 Hz, 3H), 2.38 (s, 3H), 2.49 (m, 2H), 2.60 (m, 2H), 3.70 (m, 2H), 3.91 (m, 2H) , 5.01 (br s, 2H), 6.02 (q, J = 6.6 Hz, 1H), 6.93-7.12 (m, 2H), 7.49 (dd, J = 0, 8, 7.7 Hz, 1H), 7.58 (dd, J = 0.9, 8.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1 H) 488 I- 520 Χφ çAv XxP NH, {6'-amino-5 '- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] [3,3' 'bipyridinyl-5yl} - (4-methylpiperazin-1 -II) methanone 0.134 16 (CDCb) d 1.85 (d, J = 6.6 Hz, 3H), 2.44 (s, 3H), 2.57 (m, 4H), 3.59 (m, 2H), 3.91 (m, 2H), 5.02 (brs, 2H), 5.97 (q, J = 6.4 Hz, 1H), 6.96-7.14 (m, 3H) 7.74 (s, 1H), 7.87 (br s, 1H), 8.57 (brs, 1H), 8.71 (brs, 1H), 488

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 521 Άτ {6'-amino-5 '- [1- (2chloro-3,6-difluorophenyl) -ethoxy] [2,3' 'bipyridinyl-6yl} - (4-methylpiperazin-1 -II) methanone 0.0716 16 (CDCb) d 1.86 (d, J = 6.6 Hz, 3H), 2.45 (s, 3H), 2.62 (brs, 2H), 2.69 (brs, 2H), 3.82 (brs, 2H), 3.95 (brs, 2H), 4.97 (brs, 2H), 5.98 (q, J = 6.5 Hz, 1H), 6.96-7.14 (m, 3H), 7.71 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 2.3, 8.3 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 488 I- 522 OXO ^f tV ^oJ Y Ah, {6-amino-5- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] - [3,4 ’] bipyridinyl-2yl} - (4-methylpiperazin-1 -II) methanone 0.0626 16 (CDCb) d 1.86 (d, J = 6.6 Hz, 3H), 2.45 (s, 3H), 2.62 (brs, 2H), 2.70 (brs, 2H), 3.77 (brs, 2H), 3.96 (brs, 2H), 5.03 (brs, 2H), 5.99 (q, J = 6.7 Hz, 1H), 6.96-7.14 (m, 2H), 7.16 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 2.0, 5.3 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 4.8 Hz, 1H), 488 I- 523 the LA LA _to NH, 5 ’- [1- (2,6-dichloro- 3-fluoro-phenyl) ethoxy] [2,3 ’] bipyridinyl-6ylamine 0.0677 16 (CDCb) d 1.87 (d, J = 6.6 Hz, 1H), 5.20 (brs, 2H), 6.23 (q, J = 6.7 Hz, 1H), 7.04 (t , J = 8.4 Hz, 1H), 7.15 (dd, J = 4.8, 6.6 Hz, 1H), 7.29 (dd, J = 5.1.9.3 Hz, 1H), 7, 51 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.67 (td, J = 7.8, 1.8 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.60 (d, J = 3.9 Hz, 1H), 378

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 524 9 μΐ ° i AA _F NH, 5 ’- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] [2,3’] bipyridinyl-6’ylamine 0.612 16 (CDCb) d 1.84 (d, J = 6.9 Hz, 3H), 5.14 (brs, 2H), 6.08 (q, J = 6.5 Hz, 1H), 6.93-7.10 (m, 2H), 7.16 (dd, J = 5.1, 6.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.65- 7.70 (m, 2H), 8.24 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H) 362 1- 525 Q * nh> 5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] [3,3 ’] bipyridinyl-6ylamine 0.0777 16 (CDCb) d 1.87 (d, J = 6.6 Hz 3H), 5.37 (brs, 2H), 6.00 (q, J = 6.5 Hz, 1H), 6.97-7.15 (m, 3H), 7.34 (dd, J = 4.7, 7.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.65 (s, 1H), 362 1- 526 Ν '· * ». PsÂAoV ^l AA _F NH, 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5-pyrimidin5-yl-pyridin-2ylamine 0.552 16 (CDCb) d 1.87 (d, J = 6.6 Hz, 3H), 5.16 (brs, 2H), 5.98 (q, J = 6.5 Hz, 1H), 6.96-7.14 (m, 3H), 7.86 (s, 1H), 8.77 (s, 2H), 9.14 (s, 1H), 363 1- 527 {6'-amino-5 '- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] [2,3' 'bipyridinyl-5yl} - (4-methylpiperazin-1 -II) methanone 0.0385 16 (CDCb) d 1.87 (d, J = 6.6 Hz, 3H), 2.38 (s, 3H), 2.51 (brs, 4H), 3.62 (brs, 2H), 3.81 (brs, 2H), 5.13 (brs, 2H), 6.21 (q, J = 6.7 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.30 (dd, J = 4.8, 8.7 Hz, 1H), 7.75 (dd, J = 1 , 9, 8.2 Hz, 1H), 8.28 (s, 1H), 8.64 (s, 1H), 504 1- 528 .N .. O CLuO cc /. 5- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] [3,4 ’] bipyridinyl-6ylamine 0.0659 16 (CDCb) d 1.84 (d, J = 6 Hz, 3H), 5.13 (brs, 2H), 5.97 (q, J = 6.5 Hz, 1H), 6.95-7.10 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 6 Hz, 2H), 7.95 (d, J = 2 Hz, 1H), 8.58 (d, J = 5.6 Hz, 2H), 362

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Table 2 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 529 CFjCOjH 5-benciloxy-3- [1 (2-chloro-3,6difluoro-phenyl) ethoxy] -pyridin-2ylamine 2.58 17 (CDCb) d 1.84 (d, 3H), 4.88 (s, 2H), 5.89 (q, 1H), 6.79 (d, 1H), 6, + 1 (d, 1H), 7.01 (dt, 1H), 7.11.7.17 (m, 1H), 7.28 - 7.40 (m, 5H), 391 1- 530 NH, 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- (2-ethylbutoxy-pyridin-2ylamine 4.08 17 385 1- 531 OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- (3-methylbutoxy-pyridin-2ylamine 2.4 17 371 I- 532 P 'THE 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5-butoxypyridin-2-ylamine 1.94 17 357 I- 533 kXAp ksA _F NH, 1 OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5-propoxypyridin-2-ylamine 0.672 17 343 I- 534 1 OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5cyclohexylmethoxypyridin-2-ylamine 5.97 17 397 I- 535 L.F 1 oyS 6-amino-5- [1- (2chloro-3,6-difluorophenyl) -ethoxy] pyridin-3-ol 0.54 17 301

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Table 2 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) 1- 536 •THE· 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- (2cyclohexyl-ethoxy) pyridin-2-ylamine 7.5 17 411 1- 537 »« = 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5-isobutoxypyridin-2-ylamine 1.2 17 357 1- 538 1 OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5-phenethyloxypyridin-2-ylamine 2.8 17 405 1- 539 P '/ ay? ¹ OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- (pyridin-2ylmethoxy) -pyridin-2ylamine 3.2 17 392 1- 540 P 'opx i OH 3- [1- (2-chloro-3,6difluoro-phenyl) ethoxy] -5- (pyridin-4ylmethoxy) -pyridin-2ylamine 0.8 17 392 1- 541 0 (4- {6-amino-5- [1 (2,6-dichloro-3fluor-phenyl) -ethoxy] pyridin-3-yl} -phenyl) (4-methyl-piperazin1-yl) -methanone 0.079 4 as in example I- 291 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.40 (m, 4H), 7.35 (dd, 1H), 7.08 (t, 1H), 7.02 (s, 1H ), 6.17 (q, 1H), 4.98 (s, 2H), 3.82 (m, 2H), 3.62 (m, 2H), 2.52 (m, 4H), 1.88 (d, 3H), 567

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Table 3 No. Structure Name Ki (μΜ) or I (%) Ή-NMR MS m / z (M + H) Procedure 1- 542 · _{Τ δ} ç »fS VyW Μγ, HH, (4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3- II} - phenyl) - ((3R, 5S) - 3,5-dimethylpiperazin-1- II) methanone 0.023 (400 MHz, DMSO-De) d ppm 0.84 (s, 3H) 0.93- 1.10 (m, 3H) 1.80 (d, J = 6.57 Hz, 3H) 2.30 (s, 2H) 2.55 - 2.74 (m, 2 H) 3.38 - 3.49 (m, 1H) 4.32 (s, 1H) 5.96 (s, 2H) 6.14 (q, J = 6.57 Hz, 1H) 7.00 (d, J = 1.77 Hz, 1 H) 7.36 (m, 2H) 7.45 (m, 3H) 7.56 (dd, J = 8.97, 4.93 Hz, 1H) 7.88 (d, J = 1.77 Hz, 1H) 517 18/19 / 20 // 31 1- 543 A 'γΥ,? pt r * i wA U _o ÍH, (4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3- II} - phenyl) - ((3R, 5S) - 3,5-dimethylpiperazin-1- II) methanone 1.5 (400 MHz, DMSO-De) d ppm 0.84 (s, 3H) 0.93- 1.10 (m, 3H) 1.80 (d, J = 6.57 Hz, 2H) 2.30 (s, 2H) 2.55 - 2.74 (m, 2H) 3.38 - 3.49 (m, 1H) 4.32 (s, 1H) 5.96 (s, 2H) 6.14 (q, J = 6.57 Hz, 1H) 7.00 (d, J = 1.77 Hz, 1H) 7.36 (m, 2H) 7.45 (m, 3H) 7.56 (dd, J = 8.97, 4.93 Hz, 1H) 7.88 (d, J = 1.77 Hz, 1H) 517 18/19 / 20/31 1- 544 5- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - 2-fluorobenzonitrile (400 MHz, DMSO-De) d ppm 1.80 (d, J = 6.82 Hz, 3H) 6.01 (s, 2H) 6.17 (q, J = 6.57 Hz, 1H) 7, 05 (d, J = 1.77 Hz, 1H) 7.44 (t, J = 8.72 Hz, 1H) 7.55 (m, 2H) 7.79 (m, 1H) 7.89 (d, J = 1.77 Hz, 1 H ) 7.97 (dd, J = 6.06, 2.27 Hz, 1H) 420 27

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 545 jS » 4- (4- {6- amino- 5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) - piperi- din- 4- ol (400 MHz, DMSO-De) d ppm 1.49-1.65 (m, 2H) 1.75 - 1.86 (m, 3H) 1.86 - 1.98 (m, 3H) 2.53 (s, 1H) 2.88 (s, 2H) 2.99 (s, 2H) 5.84 (s, 2H) 6.11 (d, J = 6.57 Hz, 1H) 6.93 (s, 1H) 7.28- 7.38 (m, J = 8.08 Hz, 2H) 7.39 - 7.50 (m, J = 8.21.8.21 Hz, 3H) 7.57 (dd, J = 8.72, 4.93 Hz, 1H) 7.81 (s, 1H) 477 27 1- 546 0 Ul _a ϊί (4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) - piperidin-1- II) - methanone 0.057 (400 MHz, DMSO-De) d ppm 1.43 - 1.56 (m, 4H) 1.61 (d, J = 3.79 Hz, 4H) 1.81 (d, J = 6.57 Hz, 3H) 3.51 (s, 2H) 5.94 (s, 2H) 6.15 (d, J = 6.82 Hz, 1H) 7.00 (d, J = 1.77 Hz , 1H) 7.28-7.41 (m, 2H) 7.40 - 7.50 (m, 3H) 7.57 (dd, J = 9.09, 5.05 Hz, 1H) 7.87 (d, J = 2.02 Hz, 1H) 488 20 1- 547 (4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) - pyrrolidin-1- II) - methanone 0.067 (400 MHz, DMSO-D6) d ppm 1.73 - 1.93 (m, 7H) 3.39 - 3.52 (m, 4H) 5.96 (s, 2H) 6.07 - 6.20 ( m, J = 6.82 Hz, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.39 - 7.47 (m, 3H) 7.52 (d, 2H) 7.56 ( dd, J = 9.09, 5.05 Hz, 1H) 7.82 - 7.92 (m, J = 1.77 Hz, 1H) 474 20

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 548 OyO-CH, Ç 'ÇH. fS V * - _{c |} NH, Methyl ester gave 4- {6- amino-5- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] pyridin-3- II} methyl-benzoic acid 17% (400 MHz, CHLOROPHORM-D) d ppm 1.77 - 1.88 (m, 3H) 2.11 (s, 3H) 3.91 (s, 3H) 4.90 (s, 2H) 6.02 (d, J = 6.82 Hz, 1H) 6.69 (d, J = 1.77 Hz, 1H) 7.00-7.09 (m, 1H) 7.14 (d, J = 7.83 Hz, 1H) 7.26- 7.31 (m, 1H) 7.59 (d, J = 1.77 Hz, 1H) 7.83 (dd, J = 7.96, 1.39 Hz, 1H) 7.88 (s, 1H) 450 19 1- 549 P JL XJlÍi KA, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- [4- (dimethyl-piperazin1- ylmethyl) - phenyl] pyridin-2-ylamine 0.095 (400 MHz, DMSO-De) d ppm 0.84 - 0.96 (m, 6H) 1.44-1.61 (m, 2H) 1.72-1.83 (m, 3H) 2.582.70 ( m, 2H) 2.71 - 2.84 (m, 4H) 5.76 - 5.92 (m, 2H) 6.02 - 6.18 (m, 1H) 6.88-7.01 (m, 1H) 7.25 (d, 2H) 7.32 (d, 2H) 7.38-7.49 (m, 1H) 7.507.64 (m, 2H) 7.76- 7.88 (m, 1H) 503 28 1- 550 • w- oX HAeAAyCH. (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - 3,5-dimethoxyphenyl) - (dimethylpiperazin-1- II) methanone 15% (400 MHz, DMSO-De) d ppm 0.77-0.91 (m, 3H) 1.00 (s, 3H) 1.75 (d, J = 6.82 Hz, 3H) 2.16-2.30 (m, J = 12.63 Hz, 3H) 2.64-2.76 (m, 3H) 3.54 (s, 6H) 4.25-4.40 (m, 1H) 5.69 (s, 2H) 5.91 (q, J = 6.74 Hz, 1H) 6,546.67 (m, 3H) 7.37- 7.43 (m, 1H) 7.43-7.51 (m, 1H) 7.51-7.60 (m, 1H) 577 19/20

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 551 Sry ογ * N't (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - 2-fluorophenyl) (dimethyl-piperazin-1- II) - methanone 0.091 (400 MHz, DMSO-De) d ppm 0.80 - 0.96 (m, 3H) 1.06 (s, 3H) 1.80 (d, J = 6.57 Hz, 3H) 2.26-2 .42 (m, J = 1.52 Hz, 2H) 2.61 2.85 (m, J = 1.77 Hz, 3H) 4.35-4.47 (m, J = 6.32 Hz, 1H) 6.06 (s, 2H) 6.16 ( q, J = 6.57 Hz, 1H) 7.02 (s, 1H) 7.27- 7.40 (m, 3H) 7.407.49 (m, J = 8.72, 8.72 Hz, 2H) 7.51-7.62 (m, J = 8.84, 5.05 Hz, 1H) 7.93 (s, 1H) 535 19/20 I- 552 Çb, THE (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - 3-fluorophenyl) (dimethyl-piperazin-1- II) - methanone 0.2237 (400 MHz, DMSO-De) d ppm 0.83 - 1.00 (m, 3H) 1.02 - 1.17 (m, 3H) 1.78 (d, 3H) 2.70-2.98 ( m, 6H) 4.36 - 4.50 (m, 1H) 6.01-6.10 (m, 2H) 6.10- 6.22 (m, 1H) 6.96-7.04 (m, 1H) 7.06 - 7.15 (m, 1H) 7.16 7.23 (m, 1H) 7.30-7.39 (m, 1H) 7.40- 7.49 (m, 1H) 7.50-7, 59 (m, 1H) 7.86-7.98 (m, 1H) 535 19/20 I- 553 ας Ϊ T'JLl (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - 3-methyl-phenyl) (dimethyl-piperazin-1- II) - methanone 0.2593 (400 MHz, DMSO-De) d ppm 0.88 (s, 3H) 1.01 (s, 3H) 1.77 (d, J = 6.57 Hz, 3H) 1.96 (s, 3H) 2.31 (s, 1H) 2.73 (s, 3H) 3.50 (s, 2H) 4.35 (s, 1H) 5.89 (s, 2H) 6.00 (q, J = 6.57 Hz, 1H) 6.60 (s, 1H) 7.01-7.12 (m, J = 7.83Hz 1H) 7.12 - 7.28 (m, 2H) 7.37 - 7, 63 (m, 3H) 531 19/20

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 554 CHj ΥΆ í Τ'A ¹ ** » (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) ((2R, 6S) - 2,6-dimethyl-morpholin4-II) - methanone 0.1407 (400 MHz, DMSO-De) d ppm 1.00 - 1.31 (m, 4H) 1.87 (d, J = 6.82Hz, 3H) 3.37 - 3.40 (m, 6H) 3, 55- 3.65 (m, 2H) 6.01 - 6.05 (m, 2H) 6.21 (q, J = 6.57 Hz, 1H) 7.07 (d, J = 1.77 Hz, 1H) 7.45- 7.55 (m, 5H) 7.63 (dd, J = 8.84, 5.05 Hz, 1H) 7.92- 7.98 (m, 1H) 518 19 1- 555 ° L 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2etoxy-phenyl) - pyridin-2-ylamine 22% (400 MHz, DMSO-De) d ppm 1.36 (t, J = 6.82Hz, 3H) 1.95 (d, J = 6.57 Hz, 3H) 4.08 - 4.16 (m, 2H) 5.91 -5.95 (m, 2H) 6.16 (q, J = 6.57 Hz, 1H) 7.08 - 7.13 (m, 2H) 7.19 (d, J = 7.83Hz, 1H) 7.27 (d, d, J = 7.58, 1.77 Hz, 1H) 7.40 (t, J = 8.59 Hz, 1H) 7.62 (t, J = 8.59 Hz, 1H) 7.73 (dd, J = 9.09, 5.05 Hz, 1H) 7.84 (d, J = 1.77 Hz, 1H) 421 19 1- 556 CH- AAV <A _CI NH, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,5-dimethoxy-phenyl) pyridin-2-ylamine 0.5746 (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.57 Hz, 3H) 3.57 - 3.58 (m, 3H) 3.74 - 3.75 (m, 3H) 5 , 82- 5.86 (m, 2H) 6.03 (q, J = 6.57 Hz, 1H) 6.72 (d, J = 3.28 Hz, 1H) 6.84 (dd, J = 8.84, 3.03Hz, 1H) 6.89 (d, J = 1.77 Hz, 1H) 6.98 (d, J = 9.09 Hz, 1H) 7.50 (t, J = 8.59 Hz, 1H) 7.61 (dd, J = 8.84, 4.80 Hz, 1H) 7.66 (d, J = 1.77 Hz, 1H) 437 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 557 o-CH, LÁq nh, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,4-dimethoxy-phenyl) pyridin-2-ylamine 0.2172 (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.82Hz, 3H) 3.64 - 3.67 (m, 3H) 3.81 - 3.84 (m, 3H) 5, 74 - 8.78 (m, 2H) 6.03 (q, J = 6.57 Hz, 1H) 6.59 (dd, J = 8.34, 2.27 Hz, 1H) 6.64 (d, J = 2.53 Hz, 1H) 6 .88 (d, J = 1.77 Hz, 1H) 7.10 (d, J = 8.34 Hz, IH) 7.53 (t, J = 8.59 Hz, 1H) 7.58 (d, J = 1.77 Hz, 1H) 7.63 (d, d, J = 8.84, 5.05 Hz, 1H) 437 19 1- 558 Η, Ο.θΧΧο '^ 9 ÇH | IS ** <s 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,6-dimethoxy-phenyl) pyridin-2-ylamine 2% (400 MHz, DMSO-De) d ppm 1.81 (d, J = 6.82 Hz, 3H) 3.58 - 3.59 (m, 6 H) 5.68 - 5.69 (m, 2H) 5.96 (q, J = 6.82 Hz, 1H) 6.63 (d, J = 1.77 Hz, 1H) 6.71 (d, J = 8.34 Hz, 2H) 7.26 (t, J = 8.34 Hz, 1H) 7.42 (d, J = 1.52 Hz, 1H) 7.52 (t, J = 8.59 Hz, 1H) 7.61 (dd, J = 8.84, 5.05 Hz, 1H) 437 19 1- 559 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2trifluoromethylphenyl) - pyridin-2ylamine 4% (400 MHz, DMSO-De) d ppm 1.78 (d, J = 6.57 Hz, 3H) 5.91 - 5.99 (m, 3H) 6.59 - 6.60 (m, 1H) 7.26 (d, J = 7.58 Hz, 1H) 7.42- 7.48 (m, 2H) 7.50- 7.58 (m, 2H) 7.65 (t, J = 7.33 Hz, 1H) 7.75 (d, J = 7.83 Hz, 1H) 445 19 1- 560 3- (2-chloro-phenyl) - 3- [1- (2,6-dichloro-3-fluorophenyl) - ethoxy] pyridin-2-ylamine 24% (400 MHz, DMSO-De) d ppm 1.79 (d, J = 6.82 Hz, 3H) 5.96 - 6.03 (m, 3H) 6.75 (d, J = 1.77 Hz, 1H) 7.27- 7.38 (m, 3H) 7.42 - 7.49 (m, 2H) 7.52- 7.57 (m, 2H) 411 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 561 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2trifluoromethoxyphenyl) - pyridin-2ylamine 14% (400 MHz, DMSO-De) d ppm 1.74 (d, J = 6.82 Hz, 3H) 5.92 - 5.98 (m, 3H) 6.74 (d, J = 1.77 Hz, 1H) 7.29 - 7.43 (m, 5H) 7.50 (dd, J = 9.09, 5.05 Hz, 1H) 7.56 (d, J = 1.77 Hz, 1H) 461 19 I- 562 c, çh, AA Sh. I- (2- {6- amino5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - pyridin-3yl} - phenyl) - ethanone 8% (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.82 Hz, 3H) 1.92 - 1.93 (m, 3H) 6.01 - 6.07 (m, 3H) 6.59 (d, J = 2.02 Hz, 1H) 7.26 (d, J = 7.83 Hz, 1H) 7.45 (t, J = 7.33 Hz, 1H) 7.48- 7.51 (m, 1H) 7.52- 7.58 (m, 3H) 7.61 (dd, J = 8.84, 5.05 Hz, 1H) 419 19 I- 563 F Ϊ píS, Ύι ° t 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2trifluoromethoxyphenyl) - pyridin-2ylamine 0.4322 (400 MHz, DMSO-De) d ppm 1.71 (d, J = 6.57 Hz, 3H) 5.88 - 5.90 (m, 2H) 5.96 (q, J = 6.82 Hz, 1H) 6.76 - 6.78 (m, 1H) 7.10 - 7.16 (m, 2H) 7.19- 7.28 (m, 2H) 7.36 (t, J = 8.59 Hz, 1H) 7.47 (dd, J = 8.84, 4.80 Hz, 1H) 7.60- 7.63 (m, 1H) 395 19 I- 564 The α çn, A ® yeah, (2- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3yl} - phenyl) - methanol 21% (400 MHz, DMSO-De) d ppm 1.79 (d, J = 6.57 Hz, 3H) 4.20 (t, J = 5.05 Hz, 2H) 5.03 (t, J = 5.56 Hz, 1H) 5.82 - 5.83 (m, 2H) 6.02 (q, J = 6.57 Hz, 1H) 6.68 (d, J = 1.77 Hz, 1H) 7.01 (dd, J = 7.58, 1.52 Hz, 1H) 7.31 (dt, J = 7.33, 1.26 Hz, 1H) 7.46 (t, J = 8.59 Hz, 1H) 7.49 - 7.53 (m, 2H) 7.56 ( dd, J = 8.84, 5.05 Hz, 1 H) 19 407 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 565 1 '' · ^F 'liV' ^to 'Y ^N NH, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- o-tolylpyridin-2-ylamine 25% (400 MHz, DMSO-De) d ppm 1.65 (d, J = 6.57 Hz, 1H) 1.80 - 1.80 (m, 3H) 5.67 - 5.69 (m, 2H) 5.86 (q, J = 6.57 Hz, 1H) 6.45 (d, J = 1.77 Hz, 1H) 6.86 - 6.90 (m, 1H) 7.00 - 7.09 (m, 3H) 7.29 - 7.35 (m, 2H) 7.42 (dd, J = 8.84, 5.05 Hz, 1H) 391 19 1- 566 Cl ÇHj (Ύ ° T 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2methoxy-phenyl) pyridin-2-ylamine 0.2779 (400 MHz, DMSO-De) d ppm 1.84 (d, J = 6.57 Hz, 3H) 3.65 - 3.66 (m, 3H) 5.83 - 5.84 (m, 2H) 6.04 (q, J = 6.57 Hz, 1H) 0.93 (d, J = 1.77 Hz, 1H) 7.00 (dt, J = 7.33, 1.01 Hz, 1H) 7.08 (d, J = 7.83 Hz, 1H) 7.19 (dd, J = 7.58, 1.77 Hz, 1H) 7.28 - 7.34 (m, 1H) 7.53 (t, J = 8.84 Hz, 1H) 7.61 - 7.66 (m, 2H) 407 19 1- 567 Jkl Η, Ο ^ ψ ^ ΟΗ, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,6dimethyl-phenyl) pyridin-2-ylamine 0% (400 MHz, DMSO-De) d ppm 1.57 - 1.58 (m, 3H) 1.79 (d, J = 6.82 Hz, 3H) 1.97 - 1.98 (m, 3H) 5.73 - 575 (m, 2H) 5.98 (q, J = 6.57 Hz, 1H) 6.41 (d, J = 1.77 Hz, 1H) 6.99-7.11 (m, 3H) 7.25 (d, J = 1.77 Hz, 1H) 7.44 (t, J = 8.59 Hz, 1H) 7.54 (dd, J = 8.84, 5.05 Hz, 1H) 405 19 1- 568 (4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3II} - phenyl) - morpholin- 4- II- methanone 0.0525 Anal, Calcd for C24 H22 CI2 F N3 03: C, 58.79; H, 4.52; N, 8.57, Found: C, 58.39; H, 4.72; N, 8.24, 490 20

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 569 (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3yl} - 2-chlorophenyl) ((3R, 5S) - dimethyl-piperazin-1il) - methanone 0.0478 Anal, Calcd for C26 H26 CI3 F N4 02: C, 56.59; H, 4.75; N, 10.15, Found: C, 52.83; H, 5.16; N, 8.79, 1.1 eq of H20; 1.3 eq AcOH 551 19/20 1- 570 4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3yl} - 2-methyl-phenyl) ((3R, 5S) - dimethyl-piperazin-1yl) - methanone 0.225 Anal, Calc, for C27 H29 CI2 F N4 02: C, 61.02; H, 5.50; N, 10.54, Found: C, 55.99; H, 5.79; N, 9.01, 1.2 eq of H20; 1.5 eq of AcOH 531 19/20 1- 571 Λ f *, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- [4- ((2R, 6S) - 2,6-dimethylmorpholin-4-ylmethyl) - phenyl] - pyridin2-ylamine 0.2204 (4011 MHz, CHLOROPHORM - D) d ppm 1.09 (d, J = 6.32 Hz, 6H) 1.80 d, J = 6.82 Hz, 3H) 1.88 - 1.98 (m, 2H) 2.78 - 2.90 (m, 2H) 3.59-3.70 (m, 2H) 3.86 - 3.95 (m, 2H) 5.12 5.16 (m, 2H) 6.06 (q, J = 6.57 Hz, 1H) 6,947.04 (m, 2H) 7.25 (dd, J = 8.84, 4.80 Hz, 1H) 7.28- 7.34 (m, 2H) 7.36- 7.44 (m, 2H) 7.77 (d, J = 1.52 Hz, 1H) 504 28 I- 572 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (4morpholin-4-ylmethyl) - phenyl) - pyridin2-ylamine 0.0554 (400 MHz, CHLORINE- FORMO- D) d ppm 1.80 (d, J = 6.57 Hz, 3H) 2.51 -2.58 (m, 4H) 3.58 - 3.60 (m, 2H) 3.75 (t, J = 4.55 Hz, 4 H) 5.27 - 5.31 (m, 2H) 6.06 (q, J = 6.57 Hz, 1H) 6.95 (d, J = 1.52 Hz, 1H) 7.00 (t, J = 8.08 Hz, 1H) 7.22- 7.29 (m, 3H) 7.33- 7.37 (m, 2H) 7.74 (d, J = 1.77 Hz, 1H) 476 28

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 573 ^ Cl NH, 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - 5- (3,5-dimethyl-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.64 (d, J = 6.57 Hz, 3H) 2.08 - 2.10 (m, 6H) 5.65 - 5.68 (m, 2H) 5.93 (q, J = 6.57 Hz, 1H) 6.69 - 6.71 (m, 2H) 6.75 - 6.78 (m, 2H) 7.28 (t, J = 8.59 Hz, 1H) 7.40 (dd, J = 9.09, 4.80 Hz, 1H) 7.62 (d, J = 1.77 Hz, 1H) 405 19 1- 574 iTY ^0Kl 9 ^ÇH > fS XjL ⁰ ' ^N <A _{C |} NH, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5-m-tolylpyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.78 (d, J = 6.57 Hz, 3H) 2.27 - 228 (m, 3H) 5.80 - 5.84 (m, 2H) 6.08 (q, J = 6.57 Hz, 1H) 6.88 (d, J = 1.77 Hz, 1H) 7.02 (d, J = 7.33 Hz, 1H) 7.09-7.15 (m, 2H) 7.21 (t, J = 7.58 Hz, 1H) 7.41 (t, J = 8.59 Hz, 1H) 7.54 (dd, J = 9.9, 5.05 Hz, 1H) 7.77 (d, J = 1.77 Hz, 1H) 391 19 1- 575 o- · ^ LAc nh, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3,4-dimethoxy-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.60 (d, J = 6.57 Hz, 3H) 3.55 (d, J = 14.91 Hz, 6 H) 5.57- 5.60 (m, 2H) 5.90 (q, J = 6.57 Hz, 1H) 6.83 (d, J = 2.02 Hz, 1H) 6.65 (d, J = 1.77 Hz , 1H) 6.68 - 6.76 (m, 2H) 7.23 (t, J = 8.59 Hz, 1H) 7.36 (dd, J = 4.80, 4.04 Hz, 1H) 7.58 (d, J = 1.77 Hz, 1H) 437 19 1- 576 5- biphenyl- 3- II- 3 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 5.92 - 5.95 (m, 2H) 6.16 (q, J = 6.57 Hz, 1H) 7.01 (d, J = 1.52 Hz, 1H) 7.38- 7.59 (m, 9H) 7.69 (d, J = 7.33 Hz, 2H) 7.93 (d, J = 1.52 Hz, 1H) 453 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 577 F-P- F 3- (3,5-bis-trifluoromethyl-phenyl) - 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.84 (d, J = 6.57 Hz, 3H) 6.16 - 6.24 (m, 3H) 7.03 (d, J = 1.77 Hz, 1H) 7.45 (t, J = 8.59 Hz, 1H) 7.54 (dd, J = 9.09, 5.05 Hz, 1H) 7.92 -7.95 (m, 1H) 8.008.02 (m, 2H) 8.08 (d, J = 2.02 Hz, 1H) 513 19 1- 578 X, ci 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3,4dichloro-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.87 (d, J = 6.57 Hz, 3H) 6.09 - 6.12 (m, 2H) 6.22 (q, J = 6.57 Hz, 1H) 7.04 (d, J = 1.77 Hz, 1H) 7.46-7.53 (m, 2H) 7.62 (dd, J = 9.09, 5.05 Hz, 1H) 7.66 - 7.70 (m, 2H) 7.96 (d, J = 2.02 Hz, 1H) 446 19 1- 579 HI. f ÇH. THE] MAt / U 1- (3- {6- amino5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - pyridin-3II} - phenylethanone (400 MHz, DMSO-De) d ppm 1.76 (d, J = 6.57 Hz, 3H) 2.54 - 2.55 (m, 3H) 5.90 - 5.94 (m, 2H) 6.10 (q, J = 6.57 Hz, 1H) 6.93 (d, J = 1.77 Hz, 1H) 7.39 (t, J = 8.59 Hz, 1H) 7.46 (t, J = 7.83 Hz, 1H) 7.51 (dd, J = 9.09, 5.05 Hz, 1H) 7.63 (d, J = 8.34 Hz, 1H) 7.76 (d, J = 7.83 Hz, 1H) 7.81 -7.83 (m, 1H) 7.85 (d, J = 2.02 Hz, 1H) 419 19 1- 580 γ AW <- ^ CI ^NH > 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - 5- (3,5-difluoro-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.57 Hz, 3H) 6.06 - 6.10 (m, 2H) 6.18 (q, J = 6.57 Hz, 1H) 7.01 (d, J = 1.77 Hz, 1H) 7.06 - 7.19 (m, 3H) 7.45 (t, J = 8.84 Hz, 1H) 7.58 (dd, J = 9.09, 5.05 Hz, 1H) 7.95 (d, J = 2.02 Hz, 1H) 413 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 581 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,5dichloro-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.90 (d, J = 6.82 Hz, 3H) 6.10 (q, J = 6.57 Hz, 1H) 6.17 - 6.19 (m, 2H) 6.84 (d, J = 1.77 Hz, 1H) 7.44- 7.51 (m, 2H) 7.56 (t, J = 8.59 Hz, 1H) 7.597.70 (m, 3H) 446 19 I- 582 (4- {6-amino-5 [1- (2,6-dichloro4-trifluoromethylphenyl) - ethoxy] pyridin-3- II} phenyl) - ((3R, 5S) 3,5-dimethyl-piperazin-1- II ) - methanone Paste CHN 1.0 eq AcOH 567 18/20 I- 583 r f · P * íS «Π, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3ethoxy-phenyl) - pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.33 (t, J = 6.82 Hz, 3H) 1.82 (d, J = 6.57 Hz, 3H) 3.99 - 4.09 (m, 2H) 5.88 - 5.91 (m, 2H) 6.13 (q, J = 6.57 Hz, 1H) 6.80 (dd, J = 8.08, 2.27 Hz, 1H) 6.84 (t, J = 2.02 Hz, 1H) 6.92 (d, J = 1.77 Hz, 1H) 6.96 (d, J = 7.58 Hz, 1H) 7.26 (t, J = 7.83 Hz, 1H) 7.46 (t, J = 8.59 Hz, 1H) 7.57 (dd, J = 8.84, 5.05 Hz, 1H) 7.83 (d, J = 1.77 Hz, 1H) 421 19 I- 584 <? ' ? H »A ^f - * _t A _{5 ¥} A. _o J! _s ^> - n 5- (3-chloro-phenyl) - 3- [1- (2,6-dichloro-3-fluorophenyl) - ethoxy] pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.87 (d, J = 6.57 Hz, 3H) 6.03-6.06 (m, 2H) 6.16 -6.24 (m, 1H) 7.02 (d, J = 2.02 Hz, 1H) 7.35 (td, J = 6.82, 1.77 Hz, 1H) 7.41 - 7.53 (m, 4H) 7.62 (dd, J = 8.84, 5.05 Hz, 1H) 7.93 (d, J = 2.02Hz, 1H) 411 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 585 Air M-c NH, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (4-fluorine-3-methylphenyl) - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.58 (d, J = 6.57 Hz, 3H) 2.01 - 2.02 (m, 3H) 5.62 - 5.64 (m, 2H) 5.89 (q, J = 6.82 Hz, 1H) 6.68 (d, J = 1.77 Hz, 1H) 6.90 (t, J = 8.84 Hz, 1H) 6.96 - 7.04 (m, 2H) 7.22 (t, J = 8.59 Hz, 1H) 7.34 (dd, J = 9.09, 5.05 Hz, 1 H) 7.56 (d, J = 1.77 Hz, 1H) 409 19 1- 586 Ça ^c “· c / V 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3trifluoromethylphenyl) - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.84 (d, J = 6.57 Hz, 3H) 6.05 - 6.07 (m, 2H) 6.14 - 6.21 (m, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.46 (t, J = 8.59 Hz, 1H) 7.56 (dd, J = 8.84, 5.05 Hz, 1H) 7,597.65 (m, 3H) 7.76 - 7.80 (m, 1H) 7.95 (d, J = 1.77 Hz, 1H) 445 19 1- 587 α ch, A] ^F 'pr ° i ^N ^ A _C1 NH, 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - 5- (3-fluoro-phenyl) - pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.57 Hz, 3H) 5.98 - 6.00 (m, 2H) 6.13 - 6.20 (m, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.05 - 7.11 (m, 1H) 7.21 - 7.27 (m, 2H) 7.39- 7.49 (m, 2H) 7.59 (dd, J = 9.09, 5.05 Hz, 1H) 7.90 (d, J = 2.02 Hz, 1H) 395 19 1- 588 * ^V S * \ oCror / 7 * ct ^F 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3trifluoromethoxyphenyl) - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.60 (d, J = 6.57 Hz, 3H) 5.80-5.84 (m, 2 H) 5.90- 5.98 (m, 1H) 6.73 (d, J = 2.02 Hz, 1H) 7.00- 7.07 (m, 2H) 7.20- 7.30 (m, 3H) 7.34 (dd, J = 8.84, 4.80 Hz, 1H) 7.68 (d, J = 1.77 Hz, 1H) 461 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 589 ujm 5- benzo [1,3] dioxol-5II- 3- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.57 Hz, 3H) 5.81 - 5.83 (m, 2H) 8.03 - 6.04 (m, 2H) 6.10 - 6.17 (m, 1H) 6.83 - 6.96 (m, 4H) 7.48 (t, J = 8.84 Hz, 1H) 7.58 (dd, J = 9.09, 5.05 Hz, 1H) 7.76 (d, J = 2.02 Hz, 1H) 421 19 1- 590 Çr AW <A _cl NH, 3- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3II} - phenol (400 MHz, DMSO-De) d ppm 1.95 (d, J = 6.82 Hz, 3H) 5.98 - 6.00 (m, 2H) 6.22- 6.28 (m, 1H) 6 , 78-6.81 (m, 1H) 6.89 - 6.93 (m, 2H) 7.04 (d, J = 1.77 Hz, 1H) 7.29 (t, J = 8.08 Hz , 1H) 7.58 (t, J = 9.09, 8.59 Hz, 1H) 7.71 (dd, J = 8.84, 4.80 Hz, 1H 7.89 (d, J = 1, 77 Hz, 1H) 9.55-9.57 (m, 1H) 393 19 1- 591 ΐΑ _β NH, (3- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) - methanol (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 4.52 (d, J = 5.31 Hz, 2H) 5.165.22 (m, 1H) 5.68- 5.90 (m, 2H) 6.11 -6.17 (m, 1H) 6.96 (d, J = 1.52 Hz, 1H) 7.20- 7.28 (m, 2H) 7.31 - 7.36 (m, 2H) 7.46 (t, J = 8.84 Hz, 1H) 7.58 (dd, J = 9.0.9, 5.05 Hz, 1H) 7.83 (d, J = 1.77 Hz, 1H) 407 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 592 α 3- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - benzonitrile (400 MHz, DMSO-De) d ppm 1.88 (d, J = 6.57 Hz, 3H) 6.10-6.12 (m, 2H) 6.24 (q, J = 6.57 Hz, 1H) 7.12 (d, J = 1.77 Hz, 1H) 7.51 (t, J = 8.59 Hz, 1H) 7.607.68 (m, 2H) 7.77 (d, J = 7.83 Hz, 1H) 7.81 (d, J = 8.08 Hz, 1H) 7.94- 7.96 (m, 1H) 8.00 (d, J = 1.77 Hz, 1H) 402 19 1- 593 Çr ° ' ^CH · sW? 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3methoxy-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 3.79 - 3.80 (m, 3H) 5.91 - 5.92 (m, 2H) 6.11 - 6.16 (m, 1H) 6.81 - 6.84 (m, 1H) 6.86 - 6.89 (m, 1H) 6.93 (d, J = 1.52 Hz, 1H) 6.97 - 7.01 (m, 1H) 7.29 (t, J = 8.34, 7.83 Hz, 1H) 7.46 (t, J 8.84 Hz, 1H) 7.59 (dd, J = 9.09, 5.05 Hz, 1H) 7.85 (d, J = 1.77 Hz, 1H) 407 19 1- 594 α <Λ, α THE 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3,5 dichloro-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 6.10 - 6.12 (m, 2H) 6.16 - 6.22 (m, 1H) 7.00 (d, J = 1.77 Hz, 1H) 7.44 - 7.49 (m, 4H) 7.58 (dd, J = 9.09, 5.31 Hz, 1H) 7.95 (d, J = 2.02 Hz, 1H) 446 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 595 X LXc NH, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (2,5dimethyl-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.80 (d, J = 6.82 Hz, 3H) 1.90 - 1.93 (m, 3H) 2.24 - 2.27 (m, 3H) 5.81 - 5.83 (m, 2H) 6.00 (q, J = 6.82, 6.32 Hz, 1H) 6.57 (d, J = 1.77 Hz, 1H) 6.79- 6.82 (m, 1H) 6.98-7.03 (m, 1H) 7.10 (d, J = 7.83 Hz, 1H) 7.45- 7.52 (m, 2H) 7.58 (dd, J = 8.84, 5.05 Hz, 1H) 405 19 1- 596 IÇC-oAJ? ? X FsXXaA> ^N Υ ^ ι ⁰ ίΓ 5- (5-chloro-2-methoxy-phenyl) - 3 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.79 (d, J = 6.57 Hz, 3H) 3.61 - 3.63 (m, 3H) 5.89 - 5.91 (m, 2H) 5.97- 6.03 (m, 1H) 6.86 (d, J = 1.77 Hz 1H) 7.06 (d, J = 8.84 Hz, 1H) 7.15 (d, J = 2.78 Hz, 1H) 7.29 (dd, J = 8.84, 2.53 Hz, 1H) 7.49 (t, J = 8.59 Hz, 1H) 7.59 (dd, J = 9.09, 5.31 Hz, 1H) 7.63 (d, J = 1.77 Hz, 1H) 441 19 1- 597 p ÇH »| fS ^Γ 'ν ^ Χ · £ Γ ^ ^Λ Μ-α 5- (3-chloro-4-fluoro-phenyl) - 3- [1 (2,6-dichloro-3-fluoro-phenyl) - ethoxy] - pyridin-2-amine (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 5.98 - 6.00 (m, 2H) 6.14 - 6.20 (m, 1H) 6.98 (d, J = 1.77 Hz, 1H) 7.42 - 7.45 (m, 2H) 7.47 (d, J = 8.59 Hz, 1H) 7.55 - 7.60 (m, 2H) 7.87 (d, J = 2.02 Hz, 1H) 429 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 598 fi wAr * Wo'T nh, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (5-fluorine-2-methoxyphenyl) - pyridin-2ylamine (400 MHz, DMSO-De) d ppm 1.79 (d, J = 6.57 Hz, 3H) 3.59 - 3.60 (m, 3H) 5.88 - 5.91 (m, 2H) 6.00 (q, J = 6.82 Hz, 1H) 6.90 (d, J = 1.77 Hz, 1H) 6.99 - 7.10 (m, 3H) 7.48 (t, J = 8.84 Hz, 1H) 7.59 (dd, J = 9.09, 5.31 Hz, 1H) 7.64 (d, J = 2.02 Hz, 1H) 425 19 1- 599 ÇH, Cj ^CM > AXV 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3isopropyl-phenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.20 - 1.25 (m, 6H) 1.83 (d, J = 6.57 Hz, 3H) 2.86-2.94 (m, 1H) 5.88-5.91 (m, 2H) 6.13 (q, J = 6.32 Hz, 1H) 6.89 (d, J = 1.77 Hz, 1H) 7.11 -7.15 (m, 2H) 7.23 - 7.31 (m, 2H) 7.47 (t, J = 8.59 Hz, 1H) 7.58 (dd, J = 8.84, 4.80 Hz, 1H) 7.83 (d, J = 2.02 Hz, 1H) 419 19 1- 600 _T fjA AA.? p Λ 5- (3-chloro-4trifluoromethylphenyl) - 3- [1- (2,6dichloro-3-fluorophenyl) - ethoxy] pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 6.11 - 6.13 (m, 2H) 6.17 (q, J = 6.57 Hz, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.46 (t, J = 8.84 Hz, 1H) 7.56 (dd, J = 9.09, 5.05 Hz, 1H) 7.68 (d, J = 1.77 Hz, 1H) 7.72 (d, J = 8.59 Hz, 1H) 7.80 (dd, J = 8.34, 1.77 Hz, 1H) 7.95 (d, J = 2.02 Hz, 1H) 478.90 19

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 601 'Vk.sN XÁ. X ^Cl 4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) pyridin-2- II} benzonitrile (400 MHz, DMSO-De) d ppm 1.83 (d, J = 6.57 Hz, 3H) 6.13 - 6.22 (m, 3H) 7.06 (d, J = 177 Hz, 1H) 7.45 (t, J = 8.59 Hz, 1H) 7.57 (dd, J = 9.09, 5.05 Hz, 1H) 7.63 (d, J = 8.59 Hz, 2H) 7.84 (d, J = 8.59 Hz, 2H ) 7.97 (d, J = 1.77 Hz, 1H) 402 19 I- 602 4 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (3,4difluorophenyl) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.82 Hz, 3H) 5.96 - 6.00 (m, 2H) 6.17 (q, J = 6.57 Hz, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.22- 7.27 (m, 1H) 7.41 -7.52 (m, 3H) 7.58 (dd, J = 9.09, 5.05 Hz, 1H) 7.87 (d, J = 2.02 Hz, 1H) 413 19 I- 603 9 Ç. A | Y _n HH, (4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3- II} - phenyl) - (4methyl [1,4] diacefan1- II) - methanone 0.0095 (400 MHz, DMSO-De) d ppm 1.73 (m, 1H) 1.80 (d, J = 6.82 Hz, 3H) 1.84 (m, 1H) 2.26 (d, J = 21.98 Hz, 2H) 2.53 (m, 2H) 2.63 (m, 2H) 3.40 (m, 2H) 3.60 (m, 2H) 5.95 (s, 2H) 6.14 (d, J = 6.57 Hz, 1H) 6.99 (s, 1H) 7.36 (d, J = 7.58 Hz, 2H) 7.44 (m, 3H) 7.57 (dd, J = 8.97, 4.93 Hz, 1H) 7.86 (d, J = 1.77 Hz, 1H) 517 20 I- 604 9 ÇK> fS ^ρ 'ΧΑαΛ? ^ν wx (4- {6- amino-5 [1- (2,6-dichloro- 3- fluorophenyl) ethoxy] - pyridin- 3II} - phenyl) - [1,4] diacefan-1II-methanone 0.031 (400 MHz, DMSO-De) d ppm 1.81 (t, J = 6.19 Hz, 3H) 1.90 (m, 2H) 2.96 (m, 2H) 3.10 (d, J = 36.88 Hz, 2H) 3.45 (m, 2H) 3.7 (m, 2H) 5.96 (s, 2H) 6.14 (q, J = 6.82 Hz, 1H) 6.99 (d, J = 1.52 Hz, 1H) 7.44 (m, 5H) 7.56 (dd, J = 8.97, 4.93 Hz, 1H) 7.87 ( d, J = 1.77 Hz, 1H) 503 20/21

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 605 -O (4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3yl} - phenyl) - piperazin-1-ylmethanone 0.0475 (400 MHz, DMSO-De) d ppm 1.80 (d, J = 6.57 Hz, 3H) 2.72 (m, 4H) 3.36 (m, 2H) 3.52 (m, 2H) 5.96 (s, 2H) 6.14 (q, J = 6.74 Hz, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.37 (m, 2H) 7.44 (m, 3H) 7.57 (dd, J = 8.97, 4.93 Hz, 1H) 7.87 (d, J = 1.77 Hz, 1H) 489 20/21 1- 606 F 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5-vinylpyridin-2-ylamine 0.655 (400 MHz, CHLOROPHORM-D) d, ppm 1.83 (d, J = 6.57 Hz, 3H) 4.84 (s, 2H) 5.03 (d, J = 11.12 Hz, 1H) 5.38 (d, J = 17.43 Hz, 1H) 6.06 (q, J = 6.82 Hz, 1H) 6.49 (dd, J = 17.68, 10.86 Hz, 1H) 6.90 (d, J = 1.77 Hz, 1H) 7 , 04 (dd, J = 8.84, 7.83Hz, 1H) 7.29 (dd, J = 8.84, 4.80 Hz, 1H) 7.55 (d, J = 1.77 Hz, 1H) 327 19 1- 607 f 9% Pl Fx _t A_A _o A ^ M M- _a 1 «. (4- {6- amino-5 [1- (2,6-dichloro3-fluorophenyl) ethoxy] - pyridin-3yl} - phenyl) - ((3R4S) - 3,4-dihydroxy-pyrrolidin-1il) - methanone 0.058 (400 MHz, DMSO-De) d ppm 1.81 (d, J = 6.82 Hz, 3H) 3.28 (m, 2H) 3.54 (m, 2H) 3.97 (d, J = 4.04 Hz, 2H) 4.08 (d, J = 4.29 Hz, 2H) 5.10 (br, 2H) 5.98 ( d, 2H) 7.00 (d, J = 1.77 Hz, 1H) 7.45 (m, 3H) 7.48 (m, 2H) 7.57 (dd, J = 8.97, 4.93 Hz, 1H) 7.88 (d, J = 1.77 Hz, 1H) 506 20/21

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 608 5- [(1-benzylpyrrolidin-3-ylamine) - methyl] - 3 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-2ylamine 0% (400 MHz, DMSO-De) d ppm 1.34 (m, 1H) 1.74 (d, J = 5.94 Hz, 3H) 1.78 (m, 1H) 2.08 (m, 1H) 2.40 (m, 2H) 2.54 (m, 1H) 2.89 (m, 1H) 3.33 (s, 2H) 3.49 (s, 2H) 5.52 (s, 2H) 5.94 (q, J = 6.57 Hz, 1H) 6.68 (s, 1H) 7.27 (m, 5H) 7.36 (m, 1H) 7.39 (m, 1H) 7.48 (m, 1H) 489 23 1- 609 QyN- ^ rtH LA _and NM, 4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - N-acetidin-3II-benzamide 0.045 (400 MHz, DMSO-De) d ppm 1.80 (d, J = 6.57 Hz, 3H) 2.87 (m, 1H) 3.43 (m, 1H) 3.81 (m, 2H) 4.74 (m, 1H) 6.00 (s, 2H) 6.13 (q, J = 6.48 Hz, 1H) 6.96 (dd, J = 6.57, 1.77 Hz, 1H) 7.45 (m, 3H) 7.54 (dd, J = 8.97, 4.93 Hz, 1H) 7.87 (m, 3H) 475 20/21 1- 610 r \ ^eHí VyVf \ Z _O «H, 4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - N- N-dimethylbenzenesulfonamide 0.069 (400 MHz, CHLORINE- FORMO- D) d ppm 1.87 (d, J = 6.82 Hz, 3H) 2.72 (s, 6H) 4.99 (s, 2H) 6.12 (q, J = 6.57 Hz, 1H) 6.99 (d, J = 1.77 Hz, 1H) 7.07 (m, 1H) 7.32 (dd, J = 8.84, 4.80 Hz, 1H) 7.50 (m, 2H) 7.76 (d, J = 8.59 Hz, 2H) 7.91 (d, J = 1.77 Hz, 1H) 484 29 I- 611 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (6methoxy-1H-benzoimidazole-2- II) pyridin-2-ylamine (400 MHz, MeOD) d ppm 1.72 (d, J = 6.57 Hz, 3H) 3.69 (s, 3H) 4.78 (s, 2H) 6.13 (q, J = 6.57 Hz, 1H) 6.71 (dd, J = 8.84, 2.27 Hz, 1H) 6.88 (d, J = 2.02 Hz, 1H) 7.04 (m, 1H) 7.26 (m, 2H) 7.40 (d, J = 1.77 Hz, 1H) 8.03 (d, J = 2.02 Hz 1H) 447 24

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 612 'ΰίΙ 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (6 methoxy-1-methyl1H-benzoimidazole-2- II) - pyridin-2-ylamine (400 MHz, MeOD) d ppm 1.78 (d, J = 6.57 Hz, 3H) 3.51 (s, 3H) 3.75 (s, 3H) 6.10 (q, J = 6.32 Hz, I H) 6.90 (m, 1H) 6.92 (m, 1H) 7.13 (m, 1H) 7.35 (m, 2H) 7.80 (d, J = 7.33 Hz, 1H) 461 24 Ιδη ___.cu AO p ÇH »ifS ^f TÍjl ⁰ ' ^N 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- [4- (4methyl- [1,4] diazepano1- sulfonyl) -phenyl] pyridin-2-ylamine (400 MHz, MeOD) d ppm 1.83 (m, 2H) 1.87 (d, J = 6.57 Hz, 3H) 2.66 (m, 4H) 3.35 (m, 2H) 3.40 (m, 2H) 6.20 (q, J = 6.65 Hz, 1H) 7.02 (d, J = 1.77 Hz, 1H) 7.20 (t, J = 8.59 Hz, 1H) 7.43 (dd, J = 8.97, 4.93 Hz, 1H) 7.54 (d, J = 8.34 Hz, 2H) 7.77 (d, J = 8.59 Hz, 2H ) 7.81 (d, J = 1.26 Hz, 1H) 553 29 I- 614 hh, Carboxylic acid amide 3- [1 (2,6-dichloro-3-fluoro-phenyl) -ethoxy] - 5- (1-methyl-1H-pyrazole-4-II) pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 1.82 (d, J = 6.57 Hz, 3H) 3.92 (s, 3H) 5.96 (s, 2H) 6.17 (q, J = 6.48 Hz, 1H) 7.03 (d, J = 1.77 Hz, 1H) 7.35 (dd, J = 8.59, 1.26 Hz, 1H) 7.44 (t, J = 8.72 Hz, 1H) 7.56 (m, 2H) 7.91 (d, J = 2.02 Hz, 1H) 8.03 (d, J = 8.59 Hz, 1H) 475 26 I- 615 , CHj α çh, TXT ° <Α _α NM, 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (1methyl-1H-pyrazol-4- II) - pyridin2-ylamine (400 MHz, CHLOROPHORM - D) D ppm 1.84 (d, J = 6.82 Hz, 3H) 3.89 (s, 3H) 4.76 (s, 2H) 6.05 (q, J = 6.57 Hz, 1H) 6.84 (d, J = 1.77 Hz, 1H) 7.03 (m, 1H) 7.28 (dd,, J = 8.97, 4.93 Hz, 1H) 7.40 (s, 1H) 7.53 (s, 1H) 7.74 (d, J = 1.77 Hz, 1H) 381 19 *

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 616 (4- {6- amino-5 [1- (2-trifluoromethyl-phenyl) - ethoxy] - pyridin-3- II} phenyl) - (3,5-dimethyl-piperazin-1II) - methanone 3% (400 MHz, DMSO-De) d ppm 9.29 (d, J = 9.60 Hz, 1H) 8.63 (d, J = 10.86 Hz, 1H) 7.84- 7.94 (m, 2H) 7.72 (t, J = 7.96 Hz, 3H) 7.47 - 7.57 (m, 6H) 7.35 (s, 1H) 5.97 - 6.05 (m, 1H) 3.37 (s, 2H) 1.69 (d, J = 6.06 Hz, 3H) 1.15 (s, 5 H) 1.06 (s, 1H) 500 33 I- 617 (4- {6- amino-5 [1- (3-trifluoromethyl-phenyl) - ethoxy] - pyridin-3- II} phenyl) - (3,5-dimethyl-piperazin-1II) - methanone 2% (400 MHz, DMSO-De) d ppm 9.26 (s, 2H) 8.64 (s, 2H) 7.93 (a, 2H) 7.84 (d, J = 1.52 Hz, 2H) 7.81 (d, J = 7.58 Hz, 2H) 7.66 (s, 2H) 7.60 (d, J = 8.34 Hz, 5H) 7.53 - 7.59 (m, 2H) 7.46 (d, J = 8.34 Hz, 4H) 6.01 (q, J = 6.32 Hz, 2H) 3.32 (s, 4H) 3.03 (s, 1H) 2.75 (s, 1H) 1.61 (d, J = 6.32 Hz, 5H) 1.13 (s, 7H) 500 32 I- 618 7- [4- (3,5-dimethyl-piperazine-1carbonyl) - phenyl] 2-phenyl-4H-pyrido [3.2] [1,4] oxazi n-3-one 0% (400 MHz, DMSO-De) d ppm 8.53 (s, 2H) 8.33 (d, J = 2.02 Hz, 2H) 7.84 (d, J = 4.02 Hz, 2H) 7.80 (d, J = 8.34 Hz, 5H) 7.36 - 7.42 (m, 12H) 5.93 (s, 2H) 4.55 (s, 1 H) 3.73 (s, 3H) 3.40 (s, 6H) 1.19 (s, 10H) 444 32

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 619 A ^F ”I ifS 'yÇ-oAfH O NH. {4- [6- amino-5 (3-fluoro- 2-trifluoromethyl-benciloxy) - pyridin-3-II] phenyl} - (3,5-dimethyl-piperazin-1II) - methanone 16% (400 MHz, DMSO-De) d ppm 7.97 (d, J = 1.77 Hz, 1H) 7.79 (s, 1H) 7.66 - 7.74 (m, 3H) 7.48 (d, J = 1.77 Hz, 2H) 7.41 (d, J = 8.34 Hz, 2H) 7.24 (s, 1H) 5.91 (s, 1H) 5.40 (s, 2H) 3.61 (s, 1H) 2.61 - 2.70 (m, 3H) 2.33 (s, IH) 2.17 (s, IH) 1.95 - 2.06 (m, 1H) 1.47 (s, 1H) 1.23 (s, 7H) 1.00 (s, 3H) 0.80- 0.92 (m, 6H) 504 32 I- 620 THE {4- [6- amino-5 (2,6-difluoroorbenciloxy) - pyridin3- II] - phenyl} - (3,5dimethyl-piperazin- 1- II) - methanone 5% (400 MHz, DMSO-De) d ppm 8.02 (s, 1H) 7.96 (s, 1H) 7.85 (d, J = 8.34 Hz, 2H) 7.51 - 7.62 (m, 3H) 7.23 (t, J = 8.08 Hz, 2H) 5.43 (s, 2H) 4.09 (s, 1H) 3.37 (s, 1H) 1.40 (s, 9H) 1.14 (d, J = 2.27 Hz, 3H) 1.08 (d, J = 16.42 Hz, 3H) 454 34 I- 621 [4- (6- amino-5benciloxy-pyridin3- II) - phenyl] - (3,5dimethyl-piperazin- 1- II) - methanone 6% (400 MHz, DMSO-De) d ppm 9.35 (s, 1H) 8.70 (s, 1H) 7.96 (s, 2H) 7.78 (d, J = 8.59 Hz, 4H) 7.55 (d, J = 8.08 Hz, 5H) 7.42 (t, J = 7.20 Hz, 2H) 7.35 (t, J = 7.33 Hz, 1H) 5.40 (s, 2H) 3.39 (s, 2H) 3.16 (s, 1H) 1.20 (s, 4H) 418 3

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 622 ΦΡ (4- {6- amino-5 [1- (2-chloro-3,6difluorophenyl) ethoxy] - pyridin-3II} - phenyl) - (4- ethylpiperazin-1- II) methanone 0.375 (400 MHz, DMSO-De) d ppm 7.95 (d, J = 1.77 Hz, 1H) 7.57 (d, J = 8.34 Hz, 2H) 7.52 (s, 1H) 7.45 (d, J = 8.08 Hz, 3H) 7.25 (d, J = 1.77 Hz, 1H) 6.11 (s, 1H) 5.95 (s, 2H) 3.62 (s, 1H) 3.49 (s, 1H) 2.44 (s, 2H) 2.41 (d, J = 7.07 Hz, 4H) 1.85 (d, J = 6.32 Hz, 3H) 1.06 (t, J = 7.20 Hz, 3H) 502 4 1- 623 0 Λ ΑΛ í **! ° I [4- (6- amino-5benciloxy-pyridin- 3- II) - phenyl] - (4ethyl-piperazin-1II) - methanone 7% (400 MHz, DMSO-De) d ppm 7.91 (d, J = 2.02 Hz, 1H) 7.65 (d, J = 8.34 Hz, 2H) 7.53 (d, J = 7.33 Hz, 2H) 7.44 (d, J = 1.77 Hz, 1H) 7.37 7.42 (m, 3H) 7, 32 (t, J = 7.33 Hz, 1H) 5.94 (s, 2H) 5.25 (s, 2H) 3.60 (s, 1H) 3.38 (s, 1H) 2.302.41 (m, 5H) 0.99 (t, J = 7.20 Hz, 3H) 418 34 1- 624 PAN {4- [6- amino-5 (2-methyl-benciloxy) - pyridin-3II] - phenyl} - (3,5-dimethyl-piperazin- 1- II) - methanone 0% (400 MHz, DMSO-De) d ppm 9.40 (s, 1H) 8.77 (s, 1H) 7.98 (d, J = 1.52 Hz, 1H) 7.77 -7.88 (m, 4H) 7.57 (d, J = 8.34 Hz, 2H) 7.53 (d, J = 7.33 Hz, 1H) 7.21 - 7.31 (m, 3H) 5.37 (s, 2H) 3.39 (s, 2H) 2.37 (s, 3H) 1.20 (s, 4H) 432 34

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 625 Methyl ester of 3- {2- amino- 5- [4- (4pyrrolidin-1- IIpiperidine-1carbonyl) -phenyl] pyridin-3-yloxymethyl} - benzoic acid 6% (400 MHz, DMSO-De) d ppm 9.78 (s, 1H) 8.12 (s, 1H) 7.92 - 7.98 (m, 2H) 7.88 (d, J = 7.58 Hz, 1H) 7.74- 7.83 (m, 3H) 7.59 (t, J = 7.71 Hz, 2H) 7.46 (d, J = 8.34 Hz, 2H) 5.47 (s, 2H) 3.86 s, 3H) 3.50 (s, 2H) 3.41 (s, 1H) 3.10 (s, 2H) 2.00 (s, 3H) 1.85 (s, 2H) 1.53 (s, 2H) 516 6 1- 626 item Methyl ester gave 3- {2-amino-5- [4- (3,5-dimethyl-piperazine-1-carbonyl) phenyl] - pyridin-3yloxymethyl} - benzoic acid 0% (400 MHz, DMSO-De) d ppm 9.31 (s, 2H) 8.67 (s, 2H) 8.12 (s, 2H) 7.92 - 7.99 (m, 4H) 7.88 (d, J = 7.83 Hz, 2H) 7.75- 7.84 (m, 6H) 7.53- 7.63 (m, 6H) 5.48 (s, 4H) 3.81 - 3.91 (m, 6H) 3.39 (s, 4 H) 3.13 (s, 1H) 1.20 (s, 7H) 476 34 1- 627 = σ ° τ * .A {4- [6- amino-5 (2-methyl-benciloxy) - pyridin-3II] - phenyl} - (4-pyrrolidin-1- II- piperidin-1- II) - methanone 6% (400 MHz, DMSO-De) d ppm 9.91 (s, 1H) 7.95 (d, J = 1.52 Hz, 1H) 7.85 (s, 1H) 7.80 (d, J = 8.34 Hz, 2H) 7.53 (d, J = 7.07 Hz, 1H) 7.49 (d, J = 8.34 Hz, 2H) 7.21 - 7.31 (m, 3H) 5.36 (s, 2H) 4.56 (s, 1H) 3.68 (s, 1H) 3.51 (s, 2H) 3.41 (s, 1H) 3, 10 (s, 3H) 2.82 (s, 1H) 2.37 (s, 3H) 1.99 (s, 3H) 1.79 - 1.90 (m, 2H) 1.56 (s, 2H) 472 6

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 628 rV ° [4- (6-amino-5cyclohexylmethoxypyridin-3- II) phenyl] - (4-pyrrolidin-1- II-piperidin-1- II) - methanone 7% (400 MHz, DMSO-De) d ppm 7.90 (d, J = 1.52 Hz, 1H) 7.79 (d, J = 8.34 Hz, 3H) 7.66 (s, 1H) 7, 44- 7.55 (m, 2H) 4.03 (d, J = 6.06 Hz, 2H) 3.83 (s, 1H) 3.67 (s, 1H) 3.51 (s, 2H) 3.39 (s, 1H) 3.09 (s, 2H) 2.82 (s, 1H) 2.14 (s, 2H) 1.99 (s, 3H) 1.79 - 1.91 (m, 5H) 1.64 - 1.76 (m, 3H) 1.54 (s, 2H) 1.20 - 1.30 (m, 2H) 1.07 (d, J = 11.62 Hz, 2H) 464 6 1- 629 4- (1- [2- amino- 5- [4- (4- pyrrolidin-1- II-piperidine-1-carbonyl) - phenyl] - pyridin-3yloxy-ethyl) - [2- (3-hydroxy-phenyl) ethyl] - benzamide 7% (400 MHz, DMSO-De) d ppm 9.76 (s, 1H) 8.51 (t, J = 5.56 Hz, 1H) 7.86 (d, J = 1.52 Hz, 2H) 7.79 (d, J = 8.34 Hz, 2H) 7.63 (dd, J = 14.40 , 8.34 Hz, 5H) 7.45 (d, J = 8.34 Hz, 2H) 7.04 (t, J = 7.96 Hz, 1H) 6.55- 6.65 (m, 3H) 6.00 (d, J = 6.32 Hz, 1H) 3.49 (s, 2H) 3.34 - 3.45 (m, 3H) 3.09 (s, 3H ) 2.75 (s, 1H) 2.65 - 2.74 (m, 2H) 2.13 (s, 1H) 1.99 (s, 3H) 1.78 - 1.89 (m, 2H) 1 , 65 (d, J = 6.32 Hz, 3H) 1.52 (s, 2H) 635 6

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 630 4- (1- [2- amino- 5- [4- (4- pyrrolidin-1- II-piperidine-1-carbonyl) - phenyl] - pyridin-3yloxy-ethyl) - [2 (2,6-dichlorophenyl) - ethyl] - benza mida 3% (400 MHz, DMSO-De) d ppm 9.80 (s, 1H) 8.62 (t, J = 5.81 Hz, 1H) 7.85 (d, J = 1.26 Hz, 1H) 7.78 (d, J = 8.34 Hz, 3H) 7.62 (d, d, J = 12 , 63, 8.34 Hz, 5H) 7.39 - 7.49 (m, 4H) 7.21 - 7.30 (m, 1H) 5.98 (d, J = 6.32 Hz, 1H) 3.65 (s, 1H) 3.40 - 3.51 (m, J = 6.63, 6.63, 6.63, 6.63 Hz, 4H) 3.03 - 3.15 (m, 5H) 2.82 (s, 1H) 2.13 (s, 1H) 1.98 (s, 3H) 1,781.89 (m, 2H) 1.65 (d, J = 6.08 Hz, 3H) 1.53 (s, 2H) 688 6 1- 631 4- (1- [2- amino- 5- [4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl) - phenyl] - pyridin-3yloxy-ethyl) - (1benzyl-piperidin4-yl) - benzamide 3% (400 MHz, DMSO-De) d ppm 7.75 - 7.82 (m, 2H) 7.56 - 7.67 (m, 4H) 7.39-7.49 (m, 6H) 4.27 (d, J = 4.80 Hz, 2H) 3.92 (s, 1H) 3.49 (s, 2H) 3.37 (s, 2H) 3.07 (s, 3H) 2.12 (s, 1H) 1.92 - 2.04 (m, 4 H) 1.79 - 1.91 (m, 2H) 1.71 (d, J = 11.87 Hz, 1H) 1.59 - 1.68 (m, 3H) 1.51 (s, 2H) 688 4 I- 632 THE 4- (1- [2- amino- 5- [4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl) - phenyl] - pyridin-3yloxy-ethyl) - [3- (2oxopyrrolidin-1- il) - propyl] - benzamide 0% (400 MHz, DMSO-De) d ppm 8.39 (s, 1H) 7.77 7.85 (m, 3H) 7.61 (t, J = 8.08 Hz, 6H) 7.43 (d, J = 8.34 Hz, 2H) 5.96 (s, 1H) 3.69 (s, 2H) 3.49 (s, 3H) 3.39 (s, 2H) 3.30 (t, J = 6 , 95 Hz, 3H) 3.14- 3.22 (m, 4H) 3.09 (s, 3H) 2.18 (t, J = 8.08 Hz, 2H) 2.00 (s, 3H) 1.86 (ddd, J = 15.28 , 7.58, 7.45 Hz, 4H) 1.65 (t, J = 6.06 Hz, 5H) 1.52 (s, 2H) 640 6

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 633 yCr ™ · X zsr ο τ LAa ^NH · (4- {6- amino-5 [1- (2,6-dichloro- 3-fluorophenyl) ethoxy] - pyridin-3II} - phenyl) - (4-ethylpiperazin-1- II) methanone 0.0472 (400 MHz, DMSO-De) d ppm 9.85 (s, 1H) 7.91 (d, J = 1.77 Hz, 1H) 7.58 (dd, J = 8.97, 4.93 Hz, 1H) 7.50- 7.55 (m, 4H) 7.44 - 7.50 (m, 1H) 7.13 (d, J = 1.52 Hz, 1H) 6.27 (q, J = 6.57 Hz, 1H) 3.48 (s, 2H) 3.15 (q, J = 7.07 Hz, 3H) 3.06 (s, 2H) 1.84 (d, J = 6.57 Hz, 3H) 1.22 (t, J = 7.33 Hz, 3H) 518 6 1- 634 τ * '* ^οΛ Υί * · * qAx ¹ {4- [6- amino-5 [1- (2,6-dichlorobenciloxy) - pyridin3-II] - phenyl} - (3,5-dimethyl-piperazin-1- II) - methanone 10% (400 MHz, DMSO-De) d ppm 9.20 (s, 2H) 8.66 (s, 2H) 7.91 - 8.00 (m, 5H) 7.85 (d, J = 6.82 Hz, 5H) 7.54 - 7.61 (m, 10H) 7.48 - 7.53 (m, 3H) 5.48 (s, 5H) 4.61 (s, 1H) 1.21 (d, J = 4.55 Hz, 9H) 1.15 (s, 5H) 486 34 1- 635 OyN-X p-X \ C li LXa ΛΗ, (6-amino-3aza-bicyclo [3,1,0] hex-3II) - (4- {6-amino5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - pyridin-3II } - phenyl) - methanone 0.0554 (400 MHz, DMSO-De) d ppm 8.14 (d, J = 3.54 Hz, 3H) 7.87 (s, 1H) 7.58 (dd, J = 8.97, 4.93 Hz, 1H) 7.44 - 7.53 (m, 5H) 7.12 (s, 1H) 6.25 (s, 1H) 3.95 (d, J = 11.87 Hz, 1H) 3.69 (s, 2H) 1.96 (d, J = 13.39 Hz, 2H) 1.84 (d, J = 6.57 Hz, 3H) 502 35

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 636 5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 6'- (2morpholin-4-IIethoxy) 3.3 ’] bipyridinyl-6ylamine 0.109 (400 MHz, DMSO-De) d ppm 8.20 (d, J = 2.27 Hz, 1H) 7.83 (d, J = 1.77 Hz, 1H) 7.79 (dd, J = 8.59, 2.53 Hz, 1H) 7.61 (dd, J = 8.97, 4.93 Hz, 1H) 7.49 (t, J = 8.84 Hz, 1H) 6.98 (d, J = 1.77 Hz, 1H) 6.88 (d, J = 8.59 Hz, 1H) 6.18 (q, J = 6.82 Hz, 1H) 5 , 92 (s, 2H) 4.41 (t, J = 5.81 Hz, 2H) 3.61 (m, 4H) 2.72 (t, J = 5.81 Hz, 2H) 2.47-2.52 (m, 4H) 1.85 (d, J = 6.57 Hz, 3H) 507 36 1- 637 -A W Ά. «, 6'- amino- 5'- [1 (2,6-dichloro-3fluorophenyl) - ethoxy] -1- (2-pyrrolidin- 1-yl-ethyl) 1H [3,3 '] bipyridinyl-6one 0.692 (400 MHz, DMSO-De) d ppm 7.42 - 7.52 (m, 2H) 7.25, 7.35 (m, 2H) 7.22 (t, J = 8.72 Hz, 1H) 6.64 (d, J = 1.52 Hz, 1H) 6.19 (d, J = 9.35 Hz, 1H) 5.89 (q, J = 6.74 Hz, 1H) 5.58 (s, 2H) 3.72 - 3.84 (m, 2H) 2.42 - 2.53 (m, 2H) 1.57 (d, J = 6.57 Hz, 3H) 1.39-1.50 (m, 4H) 491 35 1- 638 5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 6’- (2pyrrolidin-1-IIethoxy) [3,3 ’] bipyridinyl-6ylamine 0.094 (400 MHz, DMSO-De) d ppm 7.98 (d, J = 2.53 Hz, 1H) 7.62 (d, J = 2.02 Hz, 1H) 7.57 (dd, J = 8.59, 2.53 Hz, 1H) 7.40 (dd, J = 8.97, 4.93 Hz, 1H) 7.27 (t, J = 8.72 Hz, 1H) 6.77 (d, J = 1.77 Hz, 1H) 6.66 (d, J = 8.59 Hz, 1H) 5.97 (q, J = 6.57 Hz, 1H) 5 , 70 (s, 2H) 4.17 (t, J = 5.81 Hz, 2H) 2.56 - 2.65 (m, 2H) 1.63 (d, J = 6.82 Hz, 3H) 1 . 46 - 1.54 (m, 4H) 0.97 - 1.09 (m, 1H) 491 35

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 639 10D AAv 6'- amino- 5'- [1 (2,6-dichloro-3fluorophenyl) - ethoxy] -1- [2- (1methyl-pyrrolidin2- II) - ethyl] -1H [3,3 '] bipyridinyl- 6th 0.513 (400 MHz, DMSO-De) d ppm 7.71 (dd, J = 9.60, 1.77 Hz, 2H) 7.46- 7.56 (m, 2H) 7.42 (t, J = 8 , 72 Hz, 1H) 6.84 (s, 1H) 6.39 (d, J = 9.35 Hz, 1H) 6.10 (q, J = 6.57 Hz, 1H) 5.79 (s, 2H) 3.98-4.08 (m, 4H) 3.81 -3.92 (m, 2H) 2.85 - 2.92 (m, 2H) 2.14-2.28 (m, 7H) 1.93-2.05 (m, 5H) 1.84-1.89 (m, 2H) 1.76-1, 82 (m, 4H) 1.52 - 1.63 (m, 6H) 1.26 - 1.38 (m, 2H) 1.08 - 1.18 (m, 6H) 505 3 1- 640 ÇH, ftH, (4- {6- amino-5 [1- (2,4,6-trimethyl-phenyl) - ethoxy] pyridin-3- II} phenyl) - (4-pyrrolidin-1- II-piperidin-1- II) - methanone (400 MHz, MeOD) d, ppm 7.62 (d, J = 1.52 Hz, 1H) 7.25- 7.31 (m, 2H) 7.19- 7.25 (m, 2H) 6.73 (s, 2H) 6.65 (d, J = 1.77 Hz, 1H) 5.65 (q, J = 6.57 Hz, 1H) 4.46- 4.57 (m, 1H) 3.61 - 3.73 (m, 1H) 2.96-3.07 (m, 1H) 2.73-2.84 (m, 1H) 2.50-2.59 (m, 4H) 2.23-2.31 (m, 7H) 2.10 (s, 3H) 1.92 - 2.04 (m, 1H) 1.77 - 1.88 (m, 1H) 1.69 - 1.76 (m, 4H) 1.66 (d, J = 6.82 Hz, 3H) 1.29 - 1.40 (m, 2H) 513 6

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 641 (4- {6- amino-5 [1- (2-chloro-6 fluoro-phenyl) - ethoxy] - pyridin-3- II} phenyl) - (4-pyrrolidin-1- II- piperidin-1- II) - methanone (400 MHz, MeOD) d, ppm 7.66 (d, J = 2.02 Hz, 1H) 7.28- 7.39 (m, 4H) 7.12- 7.23 (m, 2H) 7.07 (d, J = 1.77 Hz, 1H) 6.92 - 7.02 (m, 1H) 5.97 (q, J = 6.06 Hz, 1H) 4.44- 4.56 (m, 1H) 3.62 - 3.74 (m, 1H) 2.96 - 3.08 (m, 1H) 2.72 - 2.84 (m, 1H) 2.48 - 2.59 (m, 4 H) 2.20 - 2.31 (m, 1H) 1.91 - 2.02 (m, 1H) 1.78 - 1.89 (m, 1H) 1.66 - 1.77 (m, 8H) 1.28 - 1.40 (m, 2H) 523 6 I- 642 0 kÀ _to k 3- [1- (2,6-dichloro-3-fluoro-phenyl) ethoxy] - 5- (4-fluoro-phenyl) - pyridin-2-ylamine (400 MHz, DMSO-De) d ppm 7.61 (d, J = 1.77 Hz, 1H) 7.38 (dd, J = 8.97, 4.93 Hz, 1H) 7.20 -7.29 (m, 3H) 6.99- 7.07 (m, 2H) 6.76 (d, J = 1.77 Hz, 1H) 5.95 (q, J = 6.65 Hz, 1H) 5.70 (s, 2H) 1.62 (d, J = 6.57 Hz, 3H) 395 1 I- 643 Χ, α Q 1 j 6'- amino- 5'- [1 (2,6-dichloro-3 fluoro-phenyl) - ethoxy] -1H [3,3 '] bipyridinyl-6ona 0.0432 (500 MHz, DMSO-De) d ppm 7.73 (s, 1H) 7.73 7.46 (m, 5H) 7.09 (d, J = 1.55 Hz, 1H) 6.42 (d, J = 9.5 Hz, 1H) 6.29 (q, J = 6.65 Hz, 1H) 1.84 (d, J = 6.60 Hz, 3H) 394 3 I- 644 5'- bromo- 5- [1 (2,6-dichloro-3 fluoro-phenyl) - ethoxy] [3,3 ’] bipyridinyl-6ona 0.1958 (300 MHz, CDCI3D1) d ppm 8.54 (d, 2H) 7.80 (m, 2H) 7.33 (m, 1H) 7.08 (m, 1H) 6.93 (s, 1H) 6.12 (q, J = 6.7 Hz, 1H) 5.041 (br, s, 2H) 1.88 (d, J = 6.7 Hz, 3H) 458 [M + 2] 3

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 645 LAq Μς 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (4dimethylaminophenyl) - pyridin-2ylamine 0.1572 (300 MHz, CDCI3D1) d ppm 7.83 (d, J = 1.87 Hz, 1H) 7.28 (m, 4H) 7.04 (m, 1H) 6.98 (d, J = 1.76 Hz, 1H) 6.75 (m, 2H) 6.11 (q, J = 6.7 Hz, 1H) 4.76 (br, s, 2H) 2.97 (s, 6H) 1.85 (d , J = 6.7 Hz, 3H) 420 3 1- 646 LA _O Ah, 5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 2'-methoxy [3,3 '] bipyridinyl-6ylamine 0.099 (300 MHz, CDCI3D1) d ppm 8.10 (s, 1H) 7.77 (s, 1H) 7.50 (m, 1H) 7.30 (m, 1H) 7.09 (m, 2H) 6.92 (m, 1H) 6.00 (d, J = 6.7 Hz, 1H) 4.91 (br, s, 2H) 3.87 (s, 3H) 1.83 (d, J = 67 Hz, 3H) MS 408 m / z 3 1- 647 3- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] - 5- (1Hindol-5- II) - pyridin-2-ylamine 0.1664 (300 MHz, CDCI3D1) d ppm 8.21 (s, IH) 7.93 (m, 1H) 7.64 (m, 1H) 7.43 (m, 1H) 7.32- 7.21 (m, 3H) 7,097,024 (m, 2H) 6.58 (m, 1H) 6.16 (m, 1H) 4.80 (s, 2H) 3.50 (s, 2H) 1.87 (d, J = 8.69 Hz, 3H) 416 3 1- 648 > w CÇ A (4- {6- amino-5 [1- (2,6-dichlorophenyl) - propoxy] pyridin-3- II} phenyl) - (3,5-dimethyl-piperazin-1II) - methanone 0.5533 (300 MHz, CDCI3D1) d ppm 7.87 (s, 1H) 7.42 (m, 4 H) 7.30 (m, 3H) 7.16 (m, 1H) 7.05 (s, 1H) 5.92 (m, 1H) 4.97 (s, 2H) 4.61 (br, s, 1H) 3.65 (br, s, 2H) 2.85 (br, s, 3H) 2.49 (br, s, 1H) 2.41 (m, 3H) 2.19 (m, 1H) 1.08 (m, 6H) 513 1

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 649 U NHi [4- (6- amino-5benciloxy-pyridin- 3- II) - phenyl] - (4pyrrolidin-1- IIpiperidin-1- II) methanone 29% (400 MHz, DMSO-De) d ppm 7.92 (d, J = 1.77 Hz, 1H) 7.68 (d, J = 8.34 Hz, 2H) 7.53 (d, J = 7.07 Hz, 2H) 7,377.46 (m, 5H) 7.33 (m, 1H) 5.96 (s, 2H) 5.25 (s, 2H) 3.49 (s 2H) 3.09 (s, 2H) 2.00 (s, 2H) 1.84 (s, 2H) 1.56 (s, 1H) 457 1 1- 650 9 ÇH. AU £ _ci 3- (2,6-dichloro3-fluorine-benciloxy) - 5-thiazole- 2-IIpyridin-2-ylamine 0.3627 (300 MHz, CDCI3-D1) d ppm 8.25 (d, J = 1.79 Hz, 1H) 7.76 (d, J = 3.30 Hz) 7.36 - 7.26 (m, 3H) 7.20 (m, 1H) 7.05 (m, 1H) 6.17 (q, J = 6.7 Hz, 1H) 6.09 (br, s, 2H) 1.86 (d, J = 6.7 Hz 3H) 384 37 1- 651 (4- {6- amino-5 [1- (2-fluor-6trifluoromethylphenyl) - ethoxy] pyridin-3- II} phenyl) - (4-pyrrolidin-1- II- piperidin-1- II) - methanone 1.5258 (400 MHz, DMSO-De) d ppm 7.93 (d, J = 1.52 Hz, 1H) 7.74- 7.82 (m, 3H) 7.71 (m, 3H) 7.62 - 7.67 (m, 3H) 7.47 (m, 4 H) 7.38 (m, 1H) 5.43 (s, 2H) 3.67 (br, s, 2H) 3.51 (br, s, 3H) 3.40 (br, s, 1H) 3.09 (br, s, 2H) 2.00 (br, s, 3H) 1.83 (br, s, 2H) 1.53 (br, s, 2H) 533 6 I- 652 h ^ -íÇn <• 4 3- (2,6-dichloro-3-fluoro-benciloxy) - 5- (1-methyl1H-imidazole- 2- II) - pyridin-2ylamine 11% (300 MHz, CDCI3-D1) d ppm 7.90 (d, J = 1.67 Hz, 1H) 7.30 (m, 2H) 7.05 (m, 3H) 6.91 (d, J = 0.98 Hz, 1H) 6.10 (q, J = 6.7 Hz, 1H) 4.99 (br, s, 2H) 3.57 (s, 3H) 1.83 (d, J = 6.7 Hz, 3H) 381 38

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 653 'AA {4- [6- amino-5 (2,4,6-trimethylbenciloxy) - pyridin- 3- II] - phenyl} - (4pyrrolidin-1- IIpiperidin-1- II) methanone 2% (400 MHz, DMSO-De) d ppm 7.92 (s, 1H) 7.90 (s, 1H) 7.84 (d, J = 8.34 Hz, 2H) 7.50 (d, J = 8.34 Hz, 2H) 6.92 (s, 2H) 5.27 (s, 2H ) 3.51 (br, s, 8H) 3.09 (br, s, 3H) 2.32 (s, 8 H) 2.25 (s, 3H) 1.99 (br, s, 2H) 1, 84 (br, s, 2H) 1.55 (br, s, 2H) 499 6 1- 654 {4- [6- amino-5 (2,3,5,6-tetramethyl-benciloxy) pyridin-3- II] phenyl} - (4-pyrrolidin-1- II- piperidin-1- II) - methanone 9% (400 MHz, DMSO-De) d ppm 9.75 (s, 1H) 7.88 (s, 2H) 7.79 (d, J = 8.34 Hz, 2H) 7.45 (d, J = 8.08 Hz, 3H) 6.97 (s, 1H) 5.28 (s, 2H) 3.64 (s, 1H) 3.45 (s, 2H) 3.34 (s, 1H) 3.04 (s, 3H) 2.15 (s, 12H) 1.94 (s, 3H) 1.79 (s, 2H) 1.50 (s, 2H) 513 6 1- 655 {4- [6- amino-5 (2,4,6-trifluorobenciloxy) - pyridin3-II] - phenyl} - (4pyrrolidin-1- IIpiperidin-1- II) methanone (400 MHz, DMSO-De) d ppm 7.83 (d, J = 2.02 Hz, 1H) 7.48 (d, J = 8.34 Hz 3H) 7.33 (d, J = 8.34 Hz, 3H) 7.24 (d, J = 1.77 Hz, 1H) 7.22 (m, 2H) 5.86 (m, 1H) 5.76 (s, 2H) 4.19 (br, s, 1H) 3.55 (br, s, 1H) 2.96 (br, s, 2H) 2.16 (br, s, 1H) 1.83 (br, s, 2H) 1.69 (br, s, 5H) 1.60 (d, J = 5.67 Hz, 5H) 1.30 (br, s, 2H) 525 6

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 656 (4- {6- amino-5 [1- (2-fluor-6trifluoromethylphenyl) - ethoxy] pyridin-3- II} phenyl) - (4-pyrrolidin-1- II- piperidin-1- II) - methanone (400 MHz, DMSO-De) d ppm 7.89 (d, J = 1.77 Hz, 1H) 7.57- 7.65 (m, 3H) 7.41 - 7.49 (m, 2H) 7.36 (d, J = 8.08 Hz, 2H) 7.19 (d, J = 1.77 Hz, 1H) 5.85 (s, 2H) 5.80 (s, 1H) 4.21 (s, 1H) 3.57 (br, s, 1H) 3.02 (s, OH) 2.22 (s, 1H) 1.80 (br, s, 2H) 1.78 (d, J = 6.3 Hz, 3H) 1.66 (s, 4H) 1.34 (s, 2H) 557 6 1- 657 VJUcH, α L ^ X? ™ Ij tn Η, Ν ^, Τ 6- amino- 5- [1 (2,6-dichloro-3 fluoro-phenyl) - ethoxy] - N-methylnicotinamidine (400 MHz, DMSO- De) δ ppm 8.82 (br, s, 1H) 7.97 (d, J = 1.77 Hz, 1H) 7.52-7.57 (m, 1H) 7.46 (t, J = 8.72 Hz, 1H) 7.05 (d, J = 1.26 Hz, 1H) 6.73 (br, s, 1H) 6.06 (quart ,, J = 6.57 Hz, 1H) 2.91 (s, 3H) 1.78 (d, J = 6.57 Hz, 3H) 357 39 1- 658 A- * ⁰ CjUcH, α Ι1χ ^ΜΗ «.A? ^K C ° 6- amino- 5- [1 (2,6-dichloro-3-fluoro-phenyl) - ethoxy] - N- (2-morpholin-4-II-ethyl) nicotinamidine (400 MHz, DMSO- De) δ ppm 9.07 (br, s, 1H) 7.94 (d, J = 1.52 Hz, 1H) 7.53 (m, 1H) 7.47 (m, 1H) 6.97 (s, 1H) 6.77 (br, s, 1H) 6.06 (s, 1 H) 3.55 (quart, J 4.29 Hz, 2H) 3.54 (m, 2H) 3.47 (m, 2H) 2.54 (t, J = 6.06 Hz, 2H) 2.42 (s, 3H) 1.78 (d, J = 6.82 Hz, 3H) 456 39

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Table 3 No. Structure Name Ki (μΜ) or I (%) ¹ H-NMR MS m / z (M + H) Procedure 1- 659 χ ^σ ° A τ fAAf (4- {6- amino-5 [1- (2,4,5-trifluorophenyl) - propoxy] pyridin-3- II} phenyl) - (4-pyrrolidin-1- II-piperidin-1- II) - methanone (400 MHz, DMSO-De) d ppm 9.84 (s, 1H) 7.91 (d, J = 1.52 Hz, 1H) 7.78 - 7.88 (m, 1H) 7.65 - 7.75 (m, 3H) 7.57 (dd, J = 10.23, 3.66 Hz, 1H) 7.46 (d, J = 8.34 Hz, 2H) 5.91 - 5.98 (m, 1H) 3.50 (s, 2H) 3.40 (s, 1H) 3.09 (s, 2H) 2.09 (dt, J = 14.08, 6.98 Hz, 2H) 1.99 (s, 2H) 1.92 (dt, J = 13.90, 6.95 Hz, 2H) 1.83 (s, 2H) 1.55 (s, 2H) 0.92 (t, J = 7.33 Hz, 3H) 540 6 1- 660 r Γ’Χ'ϊ (4- {6- amino-5 [1- (6-chloro-2-fluoro-3-methylphenyl) - ethoxy] pyridin-3- II} phenyl) - (4-pyrrolidin-1- II- piperidin-1- II) - methanone NMR (400 MHz, DMSODe) d ppm 9.84 (s, 1H) 7.95 (s, 2H) 7.65 (d, J = 8.34 Hz, 2H) 7.53 - 7.60 (m, 2H) 7.48 (s, 1H) 7.32 - 7.42 (m, 2H) 6.25 (q, J = 6.48 Hz, 1H) 3.58 (s 2H) 3.49 (s 1H) 3.18 (d, J = 5.05 Hz, 3H) 2.27 (d, J = 1.52 Hz, 5H) 2.01 - 2.13 (m, 4H) 1.89 (d, J = 6.57 Hz, 5H) 1.64 (d, 2H) 539 6 1- 661 3- (1- {2 amino- 5- [4- (4pyrrolidin-1- IIpiperidine-1carbonyl) -phenyl] pyridin-3-yloxy} ethyl) - benzoic acid (400 MHz, DMSO-De) d ppm 10.14 (s, 1H) 8.12 (s, 1H) 7.93 (s, 1H) 7.76 - 7.87 (m, 4H) 7.72 ( s, 1H) 7.65 (d, J = 8.34 Hz, 2H) 7.53 (ddd, J = 15.92, 7.83, 7.58 Hz, 2H) 7.40-7.47 (m, 3H) 6.03 - 6.10 (m, 1H) 4.55 (s, 1H) 3.64 (s, 1H) 3.47 (s, 2H) 3.38 (s, 1H) 3.07 (s, 3H) 2.13 (s, 1H) 1.98 (s, 3H) 1.78 - 1.89 (m, 3H) 1.65 (t, J = 5.68 Hz, 3H) 1.56 (s, 2H) 1.31 (d, J = 6.57 Hz, 2H) 516 6

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II-1 OH 4- [5-amino-6 (2,6dichlorobenciloxy) -pyrazin2-yl] -phenol 1.35 See example (400 MHz, DMSO-de) δ 5.61 (s, 2H), 6.09 (s, 2H), 6.79 (d, 2H), 7.45 (t, 1H), 2.56 (d , 2H), 7.76 (d, 2H), 7.99 (s, 1H) 9.46 (s, 1H) 362 II-2 4? 0 Apv 3- (2,6-dichlorobenciloxy) -5- [4 (1,1-dioxo-1À® ozothiazolidin-2-ll) phenyl] -pyrazin-2ylamine 0.82 5 See example (400 MHz, DMSO-de) δ 2.41 (m, 2H), 3.51 (m, 2H), 3.76 (m, 2H), 5.62 (s, 2H), 6.28 (s, 2H), 7.22 (m, 2H), 7.48 (m, 1H), 7.56 (m, 2H), 7.94 (m, 2H), 8.14 (s, 1H) 465 II-3 3- (2,6-dichlorobenciloxy) -5- [3- (2morpholin-4-yletoxy) -phenyl] pyrazin-2-ylamine 0.74 See example (400 MHz, DMSO-de) δ 2.45 (m, 4H), 2.71 (t, 2H), 3.56 (t, 4H), 4.15 (t, 2H), 5.61 (s, 2H), 6.32 (s, 2H), 6.86 (d, 1H), 7.29 (t, 1H), 7.46 (m, 2H), 7.52 (m, 1H), 7.55 (s, 1H), 7.57 (d, 1H), 8.16 (s, 1H) 475 II-4 _f ora 3- (2,6-dichlorobenciloxy) -5- [4- (2morpholin-4-yl-ethoxy) phenyl] -pyrazin-2ylamine 1.25 See example (400 MHz, DMSO-de) δ 2.45 (m, 4H), 2.71 (m, 2H), 3.59 (t, 4H), 4.11 (t, 2H), 5.64 (s2H), 6.18 (s, 2H ), 6.97 (d, 2H), 7.46 (t, 1H), 7.56 (d, 2H), 7.86 (d, 2H), 8.06 (s, 1H) 475 II-5 0 ApV LA _to N * 5- (4-amino-phenyl) -3 (2,6-dichlorobenciloxy) pyrazin-2ylamine 0.94 See example (400 MHz, DMSO-de) δ 5.19 (s, 2H), 5.59 (s, 2H), 5.96 (s, 2H), 6.60 (d, 2H), 7.45 (t, 1H), 7.56 (d, 2H), 7.62 (d, 2H), 7.91 (s, 1H) 361 II-6 O ^ OH A It Ί ^& Γ <Α · _α ^NH = 4- [5-amino6- (2,6dichlorobenciloxy) -pyrazin2-yl] -benzoic acid 1.75 See example (400 MHz, DMSO-de) δ 5.64 (s, 2H), 6.52 (s, 2H), 7.46 (m, 1H), 7.56 (m, 2H), 7.96 (d, 2H), 8.07 (d, 2H), 8.27 (s, 1H) 390 II-7 % {4- [5-amino-6- (2,6dichloro-benciloxy) pyrazin-2-yl] -phenyl} [(2R) -2-pyrrolidin-1 ylmethyl-pyrromidyl-1 yl] -methanone 0.24 See example (400 MHz, DMSO-de) δ 1.79 (m, 10H), 2.64 (m, 4H), 3.45 (m, 3H), 5.64 (s, 2H), 6.42 (s , 2H), 7.49 (m, 3H), 7.58 (m, 2H), 7.98 (d, 2H), 8.00 (s, 1H) 526

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 11-8 JXxxoX-N ΐΛ _α k {4- [5-amino-6- (2,6dichloro-benciloxy) pyrazin-2-yl] -phenyl} (4-pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.56 See example (400 MHz, DMSO-de) δ 1.37 (m, 2H), 1.66 (m, 4H), 1.85 (m, 2H), 2.32 (m, 2H), 2.52 (m , 4H), 3.04 (m, 2H), 3.92 (m, 1H), 5.62 (s, 2H), 6.42 (s, 2H), 7.40 (d, 2H), 7.46 (t , 1H), 7.58 (m, 2H), 8.00 (d, 2H), 8.21 (s, 1H) 526 11-9 'Y ^ o'Q kA _F «Η, 2-morpholin-4yl-ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-dichlorobenciloxy) -pyrazinyl] phenyl} -amide 1.26 See example (300 MHz, CDCb) δ 12.50 (t, 42H), 2.92 (t, 2H), 3.29 (t, 2H), 3.72 (t, 2H), 4.81 (s, 2H ), 5.67 (d, 2H), 7.05 (m, 2H), 7.20 (m, 1H), 7.28 (m, 2H), 7.90 (d, 2H), 8.04 (s, 1H) 540 II- 10 2-piperidin1-yl-ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 1.2 See example (300 MHz, CDCb) δ 1.60 (m, 2H), 1.63 (m, 4H), 2.49 (m, 4H), 2.90 (t, 2H), 3.26 (t, 2H), 4.85 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.29 (d, 2H), 7.89 (d, 2H), 8.04 (s, 1H) 538 II- 11 ? Ί ^ ζ ' 2- (4-hydroxypiperidin-1 -II) ethanesulfonic acid {4 [5-amino-6- (2-chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 0.65 See example (300 MHz, CDCb) δ 1.63 (m, 2H), 1.90 (m, 2H), 2.27 (t, 2H), 2.80 (m, 2H), 2.92 (t, 2H), 4.86 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.28 (d, 2H), 7.90 (d, 2H), 8.04 (s, 1H) 554 II- 12 2-pyrrolidin1-yl-ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 0.58 See example (300 MHz, CDCb) δ 1.83 (m, 4H), 2.56 (m, 4H), 3.04 (t, 2H), 3.28 (t, 2H), 4.91 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.27 (d, 2H), 7.88 (d, 2H), 8.03 (s, 1H) 524

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 13 2 - [(3R) -3hydroxy-pyrrolidin-1 II] - ethanesulfonic acid {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 1.59 See example (300 MHz, CDCb) δ 1.85 (m, 1H), 2.25 (m, 2H), 2.55 (m, 1H), 2.84 (d, 1H), 3.02 (m, 3H), 3.26 (m, 2H), 4.43 (m, 1H), 4.82 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.35 (d, 2H), 7.88 (d, 2H), 8.04 (s, 1H) 540 II- 14 2 - [(2S) -3hydroxymethylpyrrolidin-1 -II] - ethanesulfonic acid {4- [5 amino-6- (2-chloro3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 1.78 See example (300 MHz, CDCb) δ 1.85 (m, 4H), 2.20 (m, 1H), 2.70 (m, 2H), 3.05 (m, 2H), 3.30-3.70 (m, 3H), 3.95 (m, 1H), 4.79 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.32 (d, 2H), 7.88 (d, 2H), 8.05 (s, 1H) 554 II- 15 NH, 0 2 (cyclopropylmethylamino) ethanesulfonic acid {4- [5-amino-6 (2-chloro-3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 1.28 See example ¹ H-NMR (300 MHz, CDCb) δ 0.14 (m, 2H), 0.52 (m, 2H), 0.95 (m, 1H), 2.50 (d, 2H), 3.21 (m, 4H), 4.86 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.30 (d, 2H) , 7.89 (d, 2H), 8.04 (s, 1H) 524 II- 16 2-dimethylamino-ethanesulfonic acid {4- [5 amino-6- (2-chloro3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 0.91 See example (300 MHz, CDCb) δ 2.30 (s, 6H), 2.86 (t, 2H), 3.21 (t, 2H), 4.83 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.18 (m, 1H), 7.28 (d, 2H), 7.88 (d, 2H), 8.05 (s, 1H) 498 II- 17 2diethylamino-ethanesulfonic acid {4- [5 amino-6- (2-chloro3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 0.46 See example (300 MHz, CDCb) δ 1.08 (t, 6H), 2.61 (q, 4H), 3.03 (t, 2H), 3.23 (t, 2H), 4.80 (s, 2H ), 5.67 (d, 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.27 (d, 2H), 7.88 (d, 2H), 8.04 (s, 1H) 526

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 18 2- (4-acetylpiperacin-1 -II) ethanesulfonic acid {4 [5-amino-6- (2-chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 1.5 See example (300 MHz, CDCb) δ 2.08 (s, 3H), 2.46 (m, 4H), 2.93 (t, 2H), 3.30 (t, 2H), 3.47 (t, 2H), 3.62 (t, 2H), 4.82 (s, 2H), 5.67 (s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.28 (d, 2H), 7.91 (d, 2H), 8.05 (s, 1H) 581 II- 19 2- [4- (2-hydroxy-acetyl) piperacin-1 -II] ethanesulfonic acid {4 [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 0.45 See example (300 MHz, CDCb) δ 2.48 (t, 4H), 2.93 (t, 2H), 3.30 (m, 4H), 3.55 (brs, 1H), 3.67 (t, 2H), 4.14 (s, 2H), 4.84 (s, 2H), 5.67 (s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.27 (d, 2H), 7.92 (d, 2H), 8.05 (s, 1H) 597 II- 20 NH, 2cyclopropylaminoethanesulfonic acid {4 [5-amino-6- (2chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 1.29 See example (300 MHz, CDCb) δ 0.37 (m, 2H), 2.14 (m, 1H), 3.24 (m, 4H), 4.93 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.28 (d, 2H), 7.90 (d, 2H), 8.03 (s, 1H) 510 II- 21 2 - [(3R) -3hydroxymethylpyrrolidin-1 -II] - ethanesulfonic acid {3- [5 amino-6- (2-chloro3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 1.38 See example (300 MHz, CDCb) δ 1.602.0 (m, 5H), 2.15 (m, 1H), 2.55-2.70 (m, 2H), 2.90- 3.15 (m, 2H), 3.3-3.62 (m, 2H), 3.89 (dd, J = 3.0, 11.3 Hz, 1H), 4.92 (s, 2H), 5.66 (s, 2H), 6.957.60 (m, 5H), 7.55-7.70 (m, 2H), 7.77 (s, 1H), 8.10 (s, 1H) 554 II- 22 2- (4-hydroxypiperidin-1 -II) ethanesulfonic acid {3 [5-amino-6- (2-chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 0.7 See example (300 MHz, CDCb) δ 140- 1.60 (m, 2H), 1.75-1.88 (m, 2H), 2.21 (t, J = 9.0 Hz, 2H), 2.65-2.75 (m, 2H), 2.85-2.95 (m, 2H), 3.20-3.35 (m, 2H), 3.69 (m, 1H), 5.17 (s, 2H), 5.68 (s, 2H), 6.92-7.02 (m, 1H), 7.08-7.20 (m, 1H), 7.30-7.45 (m, 2H), 7.69 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H) 555

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 23 (Yp 'Tpx 2- (4-acetylpiperidin-1 -II) ethanesulfonic acid {3 [5-amino-6- (2-chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 2.79 See example (300 MHz, CDCb) δ 2.03 (s, 3H), 2.30-2.04 (m, 2H), 2.75-2.85 (m, 2H), 3.20-3.40 (m, 4H), 345- 3.55 (m, 2H), 5.35 (s, 2H), 5.68 (s, 2H), 6957.02 (m, 1H), 7.05-7.20 (m, 1H), 7 , 30-7.45 (m, 2H), 7.64 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 8.13 (s, 1H), 8.52 (s, 1H) 582 II- 24 2-piperidin1-yl-ethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 3.5 See example (300 MHz, CDCb) δ 1.301.60 (m, 6H), 2.30-2.45 (m, 4H), 2.75-2.90 (m, 2H), 3.15-3.30 ( m, 2H), 5.10 (s, 2H), 5.66 (s, 2H), 6.95-7.05 (m, 1H), 7.10- 7.20 (m, 1H), 7.25-7.40 (m, 2H), 7.60-7.75 (m, 2H), 8.10 (s, 1H) 539 II- 25 çrt ^ THE 2-ethylamino-ethanesulfonic acid {3- [5 amino-6- (2-chloro3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 3.7 See example (300 MHz, CDCb) δ 0.951.05 (m, 6H), 2.45-2.55 (m, 4H), 2.95-3.10 (m, 2H), 3.15-3.25 ( m, 2H), 5.11 (s, 2H), 5.67 (s, 2H), 6.90-7.15 (m, 2H), 7.20- 7.40 (m, 2H), 7.55-7.70 (m, 2H), 8.10 (s, 1H) 527 II- 26 Ό0Ύ 2-morpholin-4II-ethanesulfonic acid {3- [5-amino-6- (2chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 3.3 See example (300 MHz, CDCb) δ 2.30- 2.50 (m, 2H), 2.80-3.00 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.75 (m, 4H), 5.21 (s, 2H), 5.67 (s, 2H), 6.95-7.08 (m, 1H), 7.10- 720 (m, 1H), 7.30-7.50 (m, 2H), 7.67 (s, 1H), 7.74 (d, J = 7.5 Hz, 1 H) 8.12 (s, 1H) 541

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 27 O 2-pyrrolidin1-yl-ethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 1.8 See example (300 MHz, CDCb) δ 1,621.82 (m, 4H), 2.40-2.55 (m, 4H), 292-3.00 (m, 2H), 3.25-3.35 (m, 2H), 5.24 (s, 2H), 5.67 (s, 2H), 6.95-7.08 (m, 1H), 7.10- 720 (m, 1H), 7.25-7.40 (m, 2H), 7.63 (s, 1H), 7.73 (d, J = 7.1 Hz, 1 H) 8.12 (s, 1H) 525 II- 28 AT 2dimethylamino-ethanesulfonic acid {3- [5 amino-6- (2-chloro3,6-difluorborboxy) -pyrazin2-yl] -phenyl} -amide 2.28 See example (300 MHz, CDCb) δ 2.27 (s, 6H), 2.86 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 5.08 (s, 2H), 5.67 (s, 2H), 7.00-7.45 (m, 4H), 7.65-7.75 (m, 2H), 8.11 (s, 1H) 499 II- 29 2- [4- (2hydroxy-acetyl) piperidin-1 -II] - ethanesulfonic acid {3- [5 amino-6- (2-chloro3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 1.82 See example (300 MHz, CDCb) δ 2.43 (t, 4H), 2.92 (t, 2H), 3.20 (t, 2H), 3.33 (t, 2H), 3.54 (brs, 1H), 3.61 (t, 2H), 4.08 (s, 2H), 5.18 (brs, 2H), 5.67 (s, 2H), 7.007.45 (m, 4H) , 7.65-7.75 (m, 2H), 8.11 (s, 1H) 597 smooth 2 (cyclopropylmethylamino) - ethanesulfonic acid {3- [5-amino6- (2-chloro-3,6difluoro-benciloxy) pyrazin-2-yl] -phenyl} amide 1.84 See example (300 MHz, CDCb) δ 0.07 (m, 2H), 0.44 (m, 2H), 0.89 (m, 1H), 2.45 (d, 2H), 3.16 (t, 2H), 3.29 (t, 2H), 5.27 (brs, 2H), 5.67 (s, 2H), 7.07 (m, 1H), 7.20 (m, 1H), 7.41 (m, 2H), 7.65 (s, 1H), 7.77 (m, 1H), 8.12 (s, 1H) 524 II- 31 2 - [(3R) -3hydroxy-pyrrolidin-1 II] - ethanesulfonic acid {3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} -amide 2.16 See example (300 MHz, CDCb) δ 1.80 (m, 1H), 2.20 (m, 2H), 2.50 (m, 1H), 2.70-3.20 (m, 5H), 3.32 (m, 2H), 4.35 (m, 1H), 5.12 (s, 2H), 5.68 (s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.40 (m , 2H), 7.73 (m, 2H), 8.15 (s, 1H) 540

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 32 2cyclopropylaminoethanesulfonic acid {3 [5-amino-6- (2chloro-3,6-difluorbyloxy) -pyrazin2-yl] -phenyl} -amide 2.13 See example (300 MHz, CDCb) δ 0.25- 0.50 (m, 4H), 2.09 (m, 1H), 3.15-3.40 (m, 4H), 5.37 (s, 2H), 5.68 (s, 2H), 7.07 (m, 1H), 7.18 (m, 1H), 7.42 (m, 2H), 7.62 (m, 1H), 7.77 (m, 1H), 8.13 (s, 1H) 510 II- 33 tVc F 4- [5-amino-6- (2-chloro-3,6 diflúorbenciloxy) -pyrazin2-yl] -benzoic acid See example 392 II- 34 0 Α ^ _Ο Α ^ 11γΑ _{0 |} NH, F {4- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(2R) -2pyrrolidin-1 -ylmethylpyrrolidin-1 -II] methanone 0.15 See example (300 MHz, CDCb) δ 1.5- 2.2 (m, 10H), 2.65 (m, 4H), 3.50 (m, 2H), 4.42 (m, 1H), 4.86 (brs, 2H), 5.68 (d, J = 1.3 Hz, 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.57 (m, 2H), 7.96 (d, 2H), 8.12 (s, 1H) 528 II- 35 ° Ao 4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (2-pyrrolidin1-yl-ethyl) -benzamide 0.13 See example (300 MHz, CDCb) δ 1.87 (m, 4H), 2.78 (m, 4H), 2.85 (t, 2H), 3.61 (m, 2H), 4.91 (s, 2H), 5.68 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.89 (d, 2H), 7.99 (d, 2H), 8.13 (s, 1H) 489 II- 36 p 0 l. ⁿ NH: {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 0.37 See example (300 MHz, CDCb) δ 1.80240 (m, 2H), 2.24 (s, 3H), 3.30-3.90 (m, 5H), 5.71 (s, 2H), 7.25 (m, 1H), 7.35 (m, 1H), 7.60 (m, 2H), 8 , 03 (d, 2H), 8.10 (s, 1H) 461 II- 37 'ί ^ ζ' ⁰ * ^{4 N} N- [2- (4-acetylpiperacin-1-yl) -ethyl] 4- [5-amino-6- (2-chloro-3,6-difluorbyloxy) -pyrazin2-yl] -benzamide 1.35 See example (300 MHz, CDCb) δ 2.10 (s, 3H), 2.52 (m, 4H), 2.66 (t, 2H), 3.40-3.80 (m, 6H), 4.94 (s, 2H), 5.68 (s, 2H), 6.75 (brs, 1H), 7 , 05 (m, 1H), 7.20 (m, 1H), 7.84 (d, 2H), 8.00 (d, 2H) 8.14 (s, 1H) 545

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 38 4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (3-pyrrolidin- 1-yl-propyl) benzamide 0.58 See example (300 MHz, CDCb) δ 1.91 (m, 6H), 2.72 (m, 4H), 2.82 (t, 2H), 3.61 (m, 2H), 4.93 (s, 2H), 5.69 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.89 (d, 2H), 7.97 (d, 2H), 8.12 (s, 1H), 8.73 (s, 1H) 503 II- 39 X Wk {4- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 0.67 See example (300 MHz, CDCb) δ 1.70- 2.10 (m, 1H), 2.24 (s, 3H), 2.34 (s, 3H), 2.602.90 (m, 1H), 3.30-4.00 (m, 4H), 4.90 (s, 2H), 5.68 (d, 2H), 7.10 (m, 1H), 7.20 (m, 1H), 7.60 (m, 2H), 7.97 (d, 2H), 8.13 (s, 1H) 489 II- 40 □ o {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3R) -3dimethylaminopyrrolidin-1 -II] methanone 0.46 See example (300 MHz, CDCb) δ 1.80- 2.40 (m, 2H), 2.24 (s, 3H), 3.30-3.90 (m, 5H), 5.71 (s, 2H), 7.25 (m, 1H), 7.35 (m, 1H), 7.60 (m, 2H), 8.03 (d, 2H), 8.10 (s, 1H) 461 II- 41 '' άγ-χ {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (3,5-dimethyl-piperacin-1yl) -methanone 0.48 See example (300 MHz, CDCb) δ 0.9- 1.2 (m, 6H), 2.2-3.2 (m, 6H), 4.91 (s, 2H), 5.68 (s, 2H), 7.10 (m, 1H), 7.20 (m, 1H), 7.48 (d, 2H), 7.97 (d, 2H), 8.12 (s, 1H) 489 II- 42 0 TX / Th, {4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 yl) methanone 0.33 See example (300 MHz, CDCb) δ 1.60- 3.40 (m, 17H), 4.89 (s, 2H), 5.68 (d, 2H), 7.10 (m, 1H), 7.20 (m, 1H), 7.47 (d, 2H), 7.96 (d, 2H), 8.11 (s, 1H) 528 II- 43 γνυΟ 4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (3-morpholin4-yl-propyl) benzamide 0.59 See example (300 MHz, CDCb) δ 1.83 (m, 2H), 2.60 (m, 6H), 3.61 (m, 2H), 3.76 (m, 4H), 4.93 (s, 2H ), 5.70 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.88 (d, 2H), 8.00 (d, 2H), 8.14 (s, 1H) 518

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 44 4- [5-amino-6- (2-chloro-3,6-difluorborboxy) -pyrazin- 2-yl] -N- (1-methylpiperidin-4-yl) benzamide 0.5 See example (300 MHz, CDCb) δ 1.80 (m, 2H), 2.07 (m, 2H), 2.22 (m, 2H), 2.34 (s, 3H), 2.88 (m, 2H), 4.04 (m, 2H), 4.92 (s, 2H), 5.69 (d, 2H), 6.03 (d, 1H), 7, 05 (m, 1H), 7.20 (m, 1H), 7.82 (d, 2H), 7.98 (d, 2H), 8.13 (s, 1H) 489 II- 45 4- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (2-morpholin4-yl-ethyl) -benzamide 1.11 See example (300 MHz, CDCb) δ 2.68 (m, 6H), 3.60 (m, 2H), 3.75 (m, 4H), 5.72 (s, 2H), 7.25 (m, 1H), 7.35 (m, 1H), 7.88 (d, 2H), 8.05 (d, 2H), 8.12 (s, 1H) 504 II- 46 the cr 0 {4- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (4-methylpiperacin-1 -II) methanone 0.68 See example (300 MHz, CDCb) δ 2.39 (s, 3H), 2.48 (m, 4H), 3.69 (m, 4H), 4.89 (s, 2H), 5.69 (s, 2H), 7.08 (m, 1H), 7.20 (m, 1H), 7.52 (d, 2H), 7.95 (d, 2H) 8.08 (s, 1H) 474 II- 47 Çi ^OM T 1 ° T NH » 3- [5-amino6- (2-chloro-3,6difluoro-benciloxy) pyrazin-2-yl] benzoic acid See example 392 II- 48 {3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (4-methylpiperacin-1 -II] methanone 2.85 See example (300 MHz, CDCb) δ 2.33 (s, 3H), 2.46 (m, 4H), 3.68 (m, 4H), 4.86 (brs, 2H), 5.67 (s, 2H), 7.08 (m, 1H), 7.20 (m, 1H), 7.35 (d, 1H), 7.47 (t, 1H), 7.95 (m, 2H), 8.10 (s, 1H) 474 II- 49 çXo- ^ {3- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3R) -3amino-pyrrolidin-1yl] -methanone 1.02 See example (300 MHz, CDCb) δ 2.12 (m, 1H), 2.44 (m, 1H), 3.52-4.05 (m, 5H), 5.71 (s, 2H), 7.24 (m, 1H), 7.38 (m, 1H), 7.54 (m, 2H), 8.02 (d, 2H), 8.12 (m, 2H) 460

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 50 {3- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3S) -3amino-pyrrolidin-1yl] -methanone 0.91 See example (300 MHz, CDCb) δ 2.12 (m, 1H), 2.44 (m, 1H), 3.52-4.05 (m, 5H), 5.71 (s, 2H), 7.24 (m, 1H), 7.38 (m, 1H), 7.54 (m, 2H), 8.02 (d, 2H), 8.12 (m, 2H) 460 II- 51 {3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (3,5-dimethyl-piperazin-1yl) -methanone 2.56 See example (300 MHz, CDCb) δ 0.99 (brs, 3H), 1.15 (brs, 3H), 2.42 (m, 1H), 2.70 (m, 1H), 2.84 (m, 1H), 2.93 (m, 1H), 3.66 (m, 1H), 4.67 (m , 1H), 4.92 (brs, 2H), 5.66 (s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.35 (m, 1H), 7 .47 (t, 1H), 7.97 (m, 2H), 8.10 (s, 1H) 488 II- 52 3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (3-morpholin4-yl-propyl) benzamide 4.2 See example (300 MHz, CDCb) δ 1.82 (m, 2H), 2.50-2.56 (m, 2H), 3.67 (m, 6H), 4.88 (brs, 2H), 5.68 (s, 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.48 (t, 2H), 7.70 (d, 1H), 7.90 (m, 1H), 8.06 (d, 1H), 8.14 (s, 1H), 8.36 (t, J = 1.6 Hz, 1H) 519 II- 53 X-O {3- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.83 See example (300 MHz, CDCb) δ 1.60 (m, 2H), 1.80 (m, 4H), 1.86 (m, 2H), 2.00 (m, 2H), 2.32 (m, 1H ), 2.61 (m, 4H), 2.56 (m, 2H), 3.00 (m, 2H), 3.82 (m, 1H), 4.66 (m, 1H), 4.93 (br s, 2H), 5.66 (s, 2H), 7.06 (m, 1H), 7.18 (m, 1H), 7.32 (dt, 1H), 7.46 (t, 1H ), 7.70 (d, 1H), 7.97 (m, 2H), 8.09 (d, J = 3.6 Hz, 1H) 528

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) 1- 54 {3- [5-amino-6- (2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -phenyl} - [(3S) -3dimethylaminopyrrolidin-1 -II] methanone 1.45 See example (300 MHz, CDCb) δ 1.85 (m, 1H), 2.10 (m, 1H), 2.21 (s, 3H), 2.31 (s, 3H), 2.75 (m, 1H), 3.42 (m, 1H), 3.64 (m, 2H), 3.92 (m, 1H), 4.93 (brs, 2H), 5.67 (s, 2H), 7.06 (m, 1H), 7.18 (m, 1H), 7.46 (m, 2H), 7.97 (m, 1H), 8.09 (m, 2H) 488 II- 55 3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (2-pyrrolidin1-yl-ethyl) -benzamide 1.6 See example (300 MHz, CDCb) δ 1.82 (m, 1H), 2.69 (m, 4H), 2.84 (m, 2H), 3.65 (m, 2H), 4.93 (brs, 2H), 5.68 (s, 2H), 7.06 (m, 1H), 7.18 (m, 1H), 7.22 (m, 1H), 7, 49 (t, J = 7.7 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 8.06 (dt, J = 7.9 Hz, 1.5 Hz 1H), 8.13 (s, 1H), 8.38 (t, J = 1.5 Hz, 1H) 488 II- 56 ACT Vy · ®; iLA _r 3- [5-amino-6- (2-chloro-3,6-difluorborboxy) -pyrazin- 2-yl] -N- (1-methylpiperidin-4-yl) benzamide 0.9 See example (300 MHz, CDCb) δ 1.71 (m, 2H), 2.11 (m, 2H), 2.28 (t, 2H), 2.95 (m, 2H), 4.11 (m, 1H), 4.89 (s, 2H), 5.69 (s, 1H), 6.28 (m , 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.45 (t, 1H), 7.68 (d, 1H), 8.06 (d, 1H), 8.11 (s, 1H), 8.35 (s, 1H 488 II- 57 The 1I ^s * j * i * ^Zx ° Iffl, 3- [5-amino-6- (2-chloro-3,6-difluorborboxy) -pyrazin- 2-yl] -N- (1-methylpiperidin-4-yl) benzamide 0.63 See example (300 MHz, CDCb) δ 2.02 (m, 10H), 2.75 (m, 4H), 3.42 (m, 2H), 4.51 (m, 1H), 4.86 (s, 2H), 5.69 (s, 2H), 7.08 (m, 1H), 7.20 (m, 1H), 7.48 (m, 2H), 7.98 (m, 1H), 8.07 (m, 1H), 8.11 (s, 1H) 528 II- 58 oW ³ 3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (2-morpholin4-yl-ethyl) -benzamide 2.5 See example (300 MHz, CDCb) δ 2.51 (m, 4H), 2.65 (t, 2H), 3.58 (t, 2H), 3.69 (m, 4H), 5.72 (s, 2H), 7.20 (m, 1H), 7.35 (m, 2H), 7.52 (t, 1H), 7.76 (d, 1H), 8.12 (m, 2H), 8.41 (s, 1H) 504

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 59 N- [2- (4-acetylpiperacin-1-yl) -ethyl] 3- [5-amino-6- (2-chloro-3,6-difluorborboxy) -pyrazin2-yl] -benzamide 2.77 See example (300 MHz, CDCb) δ 2.08 (s, 3H), 2.59 (m, 6H), 3.57 (m, 6H), 5.71 (s, 2H), 7.21 (m, 1H), 7.37 (m, 2H), 7.50 (t, 1H), 7.75 (d, 1H), 8.08 (m, 2H), 8.39 (s, 1H) 545 II- 60 3- [5-amino-6- (2-chloro-3,6-diflúorbenciloxy) -pyrazin2-yl] -N- (2-pyrrolidin- 1-yl-propyl) benzamide 1.48 See example (300 MHz, CDCb) δ 1.79 (m, 4H), 1.88 (t, 2H), 2.65 (m, 4H), 2.78 (t, 2H), 3.65 (m, 2H), 4.86 (s, 2H), 5.69 (s, 2H), 7.06 (m, 1H), 7.21 (m, 1H), 7.45 (t, 1H), 7.68 (d, 1H), 8.06 (d, 1H), 8.16 (s, 1H), 8.40 (s, 1H), 8.69 (m, 1H) 502 II- 61 CX _cl Th, 3- (2-chloro-3,6difluoro-benciloxy) -5- (1 H-indol-5-yl) - pyrazin-2-ylamine See example 387 II- 62 φτ'χ 3- (2-chloro-3,6difluoro-benciloxy) -5- (3-pyrrolidin-1 ylmethyl-1 H-indole-5yl) -pyrazin-2-ylamine 0.35 See example (300 MHz, CDCb) δ 1.78 (m, 4H), 2.66 (m, 4H), 3.89 (s, 2H), 4.89 (s, 2H) 5.69 (s, 2H), 7.08 (m, 1H), 7.18 (m, 2H), 7.39 (d, 1H), 7.79 (d, 1H), 8.08 (s, 1H), 8.18 (s, 1H), 8, 79 (s, 1H) 470 lies O ÇT Xxjò F 3- (2-chloro-3,6difluoro-benciloxy) -5 (3-diethylaminomethyl- 1 H-indol-5-yl) pyrazin-2-ylamine 0.73 See example (300 MHz, CDCb) δ 1.11 (m, 6H), 2.69 (m, 4H), 3.80 (s, 2H), 4.69 (s, 1H), 5.77 (s, 2H), 7.02 (m, 1H), 7.21 (m, 2H), 7.45 (d, 1H), 7.89 (d, 1H), 8.22 (m , 3H) 472 II- 64 Us, X. 1- (4- {5- [5-amino-6 (2-chloro-3,6-difluorborboxy) -pyrazin- 2-yl] -1 H-indol-3ylmethyl} -piperacin-1 yl) -ethanone 1.5 See example (300 MHz, CDCb) δ 2.08 (s, 3H), 2.55 (m, 4H), 3.45 (m, 2H), 3.64 (m, 2H), 3.81 (s, 2H ), 4.78 (s, 2H), 5.71 (s, 2H), 7.08 (m, 1H), 7.18 (m, 2H), 7.31 (d, 2H), 7.79 (d, 1H), 8.04 (s, 1H), 8.22 (s, 1H), 8.49 (s, 1H) 527

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 65 3- (2-chloro-3,6difluoro-benciloxy) -5- [3- (2,6-dimethylmorpholin-4-ylmethyl) 1 H-indol-5-yl] pyrazin-2-ylamine 2.4 See example (300 MHz, CDCb) δ 1.11 (d, 6H), 1.98 (m, 2H), 2.98 (m, 2H), 3.87 (m, 4H), 4.75 (s, 2H), 5.78 (s, 2H), 7.08 (m, 1H), 7.27 (m, 2H), 7.48 (d, 1H), 7.89 (d, 1H), 8.19 (s, 1H), 8.28 (s, 2H) 514 II- 66 φς *? N- (1- {5- [5-amino6- (2-chloro-3,6difluor-benciloxy) pyrazin-2-yl] -1 Hindol-3-ylmethyl} (3S) -pyrrolidin-3-yl) acetamide 0.55 See example (300 MHz, CDCb) δ 1.69 (m, 1H), 1.88 (s, 3H), 2.39 (m, 2H), 2.75 (m, 2H), 3,, 08 (m, 1H), 3.95 (m, 2H), 4.50 (m, 1H), 4.79 (s, 2H), 5.78 (s, 2H), 6.01 (m, 1H), 7.05 (m, 1H), 7.18 (m, 2H), 7.42 (d, 1H), 7.79 (d, 1H), 8.12 (s, 1H), 8.12 (s, 1H), 8.28 (s, 1H) 527 II- 67 3- (2-Chloro-3,6difluoro-benciloxy) -5 (3-piperidin-1-ylmethyl-1 H-indole-5yl) -pyrazin-2-ylamine 0.51 See example (300 MHz, CDCb) δ 1.49 (m, 2H), 1.71 (m, 4H), 2.66 (m, 4H), 3.89 (s, 2H), 4.79 (s, 2H), 5.69 (s, 2H), 7.08 (m, 1H), 7.18 (m, 1H), 7.31 (s, 1H), 7.42 (d, 1H), 7.78 (d, 1H), 8.08 (s, 1H), 8.18 (s, 1H) , 8.69 (brs, 1H) 484 II- 68 Mlt-U J? Q F 3- (2-chloro-3,6difluoro-benciloxy) -5 (3-morpholin-4ylmethyl-1 H-indole-5yl) -pyrazin-2-ylamine 1.15 See example (300 MHz, CDCb) δ 2.72 (m, 4H), 3.80 (s, 6H), 4.73 (s, 2H), 5.73 (s, 2H), 7.06 (m, 1H), 7.20 (m, 1H), 7.46 (d, 1H), 7.80 (dd, 1H), 8.12 (s, 1H), 8.25 (s, 1H) 486 II- 69 the 0 Π ° T 3- [1- (2-chloro-3,6- difluoro-phenyl) -2methyl-propoxy] -5- [4 (2-morpholin-4-yletoxy) -phenyl] -pyrazin2-ylamine 10.5 8 See example (400 MHz, DMSO-de) δ 0.89 (d, 3H), 1.19 (d, 3H), 2.47 (m, 4H), 2.56 (m, 1H), 2.68 (t, 2H), 3.56 (t, 4H), 4.07 (t, 2H), 5.96 (d, 1H), 6.28 (s, 2H), 6.89 (d, 2H), 7.26 (m, 1H), 7.38 (m, 1H), 7.63 (d, 2H), 7.95 (m, 1H) 519

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 70 Y ** TFA 3- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] 5- [4- (2-morpholin-4yl-ethoxy) -phenyl] pyrazin-2-ylamine; compuesto con trifluoroacetic acid 0.51 See example (400 MHz, DMSO-de) δ 1.78 (d, 3H), 3.21 (m, 2H), 3.51 (m, 2H), 3.54 (m, 2H), 3.98 (m, 2H), 4.38 (t, 2H), 6.34 (brs, 2H), 6.45 (m, 1H), 6.97 (d, 2H), 7.25 (m, 1H), 7.38 (m, 1H), 7.66 (d, 2H), 7.86 (s, 1H) 491 II- 71 TFA CA _q NH_ 3- [1- (2,6-dichloro- 3,6-fluoro-phenyl) ethoxy] -5- [4- (2morpholin-4-yl-ethoxy) phenyl] -pyrazin-2ylamine; composed with trifluoracetic acid 0.3 See example (400 MHz, DMSO-de) δ 1.79 (d, 3H), 3.21 (m, 2H), 3.46 (m, 2H), 3.57 (m, 2H), 3.74 (m, 2H), 3.95 (m, 2H), 4.36 (t, 2H), 6.34 (brs, 2H) 6.49 (m, 2H), 6.94 (m, 1H), 7.37 (t, 1H), 7.48 (m, 1H), 7.66 (d, 2H), 7.98 (s, 1H) 491 II- 72 0 φΑ: N- (4- {5-amino-6 [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) methanesulfonamide See example (400 MHz, DMSO-de) δ 1.78 (d, 3H), 2.96 (s, 3H), 6.41 (m, 3H), 7.15 (d, 2H), 7.26 (m, 1H), 7.37 (m, 1H), 7.64 (d, 2H), 8.00 (s, 1H), 9.72 (s, 1H) 455 II- 73 s XpO ΦΛ 2-pyrrolidin- acid 1-yl-ethanesulfonic (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} phenyl) -amide See example (300 MHz, CDCb) δ 1.84 (m, 7H), 2.56 (m, 4H), 3.04 (m, 2H), 3.25 (m, 2H), 4.91 (brs, 2H), 6.71 (q, 1H), 6.95 (m, 2H), 7.21 (d, 2H), 7.72 (d, 2H), 7.96 (s, 1H) 538 II- 74 2- (4-hydroxypiperidin-1-IIIethanesulfonic acid (4 {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} phenyl) -amide See example (300 MHz, CDCb) δ 1.60 (m, 2H), 1.82 (m, 5H), 2.32 (m, 2H), 2.77 (m, 2H), 2.89 (t, 2H ), 3.26 (t, 2H), 3.74 (m, 1H), 5.07 (brs, 2H), 6.70 (q, 1H), 7.00 (m, 2H), 7.24 (d, 2H), 7.73 (d, 2H), 7.94 (s, 1H) 568

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 75 èr / c F piperidin-1 -IIethanesulfonic acid (4 {5-amino-6- [1- (2chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} phenyl) -amide See example (300 MHz, CDCb) δ 1.49 (m, 2H), 1.61 (m, 4H), 1.83 (d, 3H), 2.50 (m, 4H), 2.86 (m, 2H), 3.20 (m, 2H), 4.95 (brs, 2H), 6.70 (q, 1H), 7.00 (m, 2H), 7.24 (d, 2H), 7.74 (d, 2H), 7.96 (s, 1H) 552 II- 76 YpTTV 0 2 (cyclopropylmethylamino) ethanesulfonic acid (4 {5-amino-6- [1- (2chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} phenyl) -amide See example (300 MHz, CDCb) δ 0.14 (m, 2H), 0.50 (m, 2H), 0.95 (m, 1H), 1.82 (d, 3H), 2.49 (m, 2H ), 3.20 (m, 4H), 4.73 (brs, 1H), 5.02 (brs, 2H), 6.71 (q, 1H), 7.00 (m, 2H), 7.25 (d, 2H), 7.74 (d, 2H), 7.96 (s, 1H) 538 II- 77 F 2 - [(3R) -3hydroxy-pyrrolidin-1 yl] -ethanesulfonic acid (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 1.79 (m, 1H), 1.82 (d, 3H), 2.26 (m, 2H), 2.54 (m, 1H), 2.82 (m, 1H ), 3.08 (m, 1H), 3.26 (m, 2H), 4.44 (m, 1H), 4.94 (br s, 1H), 6.70 (q, 1H), 7, 00 (m, 2H), 7.29 (d, 2H), 7.73 (d, 2H), 7.96 (s, 1H) 554 II- 78 THE? F 2 - [(2S) -2hydroxymethylpyrrolidin-1 -II] ethanesulfonic acid (4 {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 1.79 (m, 4H), 1.82 (d, 3H), 2.15 (m, 1H), 2.66 (m, 2H), 2.98 (m2, H ), 3.35 (m, 1H), 3.8 (m, 1H), 3.54 (m, 1H), 3.92 (m, 1H), 4.97 (brs, 1H), 6.71 (q, 1H), 7.00 (m, 2H), 7.28 (d, 2H), 7.71 (d, 2H), 7.95 (s, 1H) 568 II- 79 f? γΜγ Αχν «Η» 2dimethylaminoethanesulfonic acid (4 {5-amino-6- [1- (2chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 1.82 (d, 3H), 2.29 (s, 6H), 2.85 (t, 2H), 3.21 (t, 2H), 5.00 (brs, 2H ), 6.71 (q, 1H) 7.00 (m, 2H), 7.23 (d, 2H), 7.74 (d, 2H), 7.96 (s, 1H) 512

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 80 2-morpholin-4yl-ethanesulfonic acid (4- {5-amino-6- [1 (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 1.82 (d, 3H), 2.48 (m, 4H), 2.90 (m, 2H), 3.27 (m, 2H), 3.71 (m, 4H ), 4.92 (brs, 2H), 6.71 (q, 1H), 7.00 (m, 2H), 7.24 (d, 2H), 7.74 (d, 2H), 7.97 (s, 1H) 554 II- 81 F 2diethylaminoethanesulfonic acid (4 {5-amino-6- [1- (2chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 1.07 (t, 6H), 1.82 (d, 3H), 2.60 (q, 4H), 3.02 (t, 2H), 3.22 (t, 2H), 4.95 (brs, 2H), 6.71 (q, 1H), 7.00 (m, 2H), 7.22 (d, 2H), 7.74 (d, 2H), 7.96 (s, 1H) 540 II- 82 9 rW? LA _to NH, 2 cyclopropylaminoethanesulfonic acid (4 {5-amino-6- [1- (2chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide See example (300 MHz, CDCb) δ 0.38 (m, 2H), 0.50 (m, 2H), 1.82 (d, H), 2.15 (m, 1H), 3.24 (m, 4H), 4.95 (brs, 2H), 6.71 (q, 1H), 7.00 (m, 2H), 7.21 (d, 2H), 7.74 (d, 2H), 7.97 (s, 1H) 540 lies qAh 3- [5-amino-6 [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -benzoic acid 1.36 See example 423 II- 84 çrSo--. 'AT' (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - [(3S) -3amino-pyrrolidin-1yl) -methanone 0.06 9 See example (300 MHz, MeOD) δ 7.84 (d, 1H), 7.71 (m, 2H), 7.38 (m, 3H), 7.10 (m, 1H), 6.60 (m, 1H), 4.86 (s, 2H), 4.20 (m, 1H), 3.45-3.89 (m, 4H), 1.82 (d, 3H), 1.34 (m, 1H), 0.89 (m, 1H) 492 II- 85 Çro · »· Us, »·. (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - [(3R) -3amino-pyrrolidin-1yl) -methanone 0.11 See example (300 MHz, MeOD) δ 7.84 (d, 1H), 7.71 (m, 2H), 7.38 (m, 3H), 7.10 (m, 1H), 6.60 (m, 1H), 4.86 (s, 2H), 4.20 (t, 1H), 3.45- 3.89 (m, 4H), 1.82 (d, 3H), 1.34 (m, 1H), 0.89 (m, 1H) 492

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 86 (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - [(2R) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.15 See example (300 MHz, CDCb) δ 8.04 (d, 1H), 7.84 (d, 2H), 7.30 (d, 2H), 7.1 (tert, 1H), 6.99 (t, 1H), 5.89 (m, 1H), 4.89 (s, 2H), 4.44 (s, 1H), 3.89 (m, 1H), 3.65 (m, 1H), 3.30 (m, 2H), 2.85 (m, 3H), 1.82 (d, 3H), 0.89-2.20 (m, 9H) 558 II- 87 N- [2- (4-Acetylpiperazin-1-yl) -ethyl] 3- (5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl) -benzamide 0.18 6 See example (300 MHz, CDCb) δ 8.04 (d, 1H), 7.99 (s, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.34 (m, 2H ), 7.15 (t, 1H), 6.72 (tert, 1H), 4.89 (s, 2H), 4.56 (m, 6H), 3.21 (d, 3H), 2.60 (t, 1H), 2.55 (dd, 1H) , 2.09 (s, 3H), 1.80 (d, 4H) 575 II- 88 (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - [(2S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.17 See example (300 MHz, MeOD) δ 8.04 (d, 1H), 7.84 (d, 2H), 7.35 (m, 3H), 7.20 (m, 1H), 6.60 (m, 1H), 4.89 (s, 2H), 4.44 (s, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 3.25 (s , 2H), 3.16 (m, 3H), 1.82 (d, 3H), 0.89- 2.32 (m, 9H) 559 II- 89 here '' όφν 3- {5-amino6- [1- (2-chloro-3,6difluoro-phenyl) -ethoxy] pyrazin-2-yl} benzoic acid See example 406 II- 90 F 3- {5-amino-6- [1- (2dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (1-methylpiperidin-4-yl) benzamide 0.21 See example (300 MHz, CDCb) δ 8.20 (s, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.44 (t, 1H), 7.01 (m, 2H), 6.78 (m, 1H), 6.20 (s, 1H), 4.98 (s, 2H), 4.09 (m, 1H), 2.97 (m, 2H), 2.39 (s, 3H), 2.29 (t, 2H), 2.12 (m, 2H), 1.90 (d, 3 H), 1.79 (m, 2H) 502

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 91 3- {5-amino-6- [1- (2dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (3-ylpyrrolidin-1 -IIpropyl) -benzamide 0.15 See example (300 MHz, CD-sOD) δ 8.15 (s, 1 H), 7.98 (s, 1H) 7.80 (d, 1H), 7.61 (d, 1H), 7.35 (m, 2H), 7.09 (t, 1H), 6.69 (m, 1H), 3.44 (t, 2H), 2.55 (m, 6H), 1.88 (d, 3H), 1.80 (m, 6H) 532 II- 92 HH, (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.15 See example (300 MHz, CD-sOD) δ 7.96 (s, 1H), 7.76 (d, 1H), 7.65 (m, 1H), 7.41 (m, 2H), 7.21 (d, 1H), 7.12 (t, 1H), 6.61 (m, 1H), 4.68 (m, 2H), 3.62 (m, 1H), 3.05 (m, 2H), 2.69 (m, 6H), 2, 45 (m, 2H), 2.12 (m, 2H), 1.86 (d, 3H), 1.48 (m, 2H) 558 II- 93 0 0 « O Δ U ° k 4- [5-amino6- (3-fluoro-2trifluoromethylbenciloxy-pyrazin2-yl] -benzoic acid See example 408 II- 94 X ^the NH, 4- [5-amino-6- (3-fluoro-2trifluoromethylbenciloxy-pyrazin2-yl] -N- (2-morpholin4-yl-ethyl) -benzamide 0.22 See example (300 MHz, CDCb) δ 8.14 (s, 1H), 7.92 (d, 2H), 7.84 (d, 2H), 7.50 (m, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.75 (s, 1H), 5.70 (s, 2H), 4.97 (s, 2H), 3.74 (m, 4H), 3.58 (m, 2H), 2.62 (m, 2H), 2.52 (s, 4H) 520 II- 95 X. CC ° V Y ^ CF, 4- [5-amino-6- (3-fluoro-2trifluoromethylbenciloxy-pyrazin2-yl] -N- (1-methylpiperidin-4-yl) benzamide 0.08 1 See example (300 MHz, CDCb) δ 8.14 (s, 1H), 7.92 (d, 2H), 7.84 (d, 2H), 7.50 (m, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.04 (d, 1H), 5.75 (s, 2H), 5.01 (s, 2H), 4.0 (m, 1H), 2.85 (d, 2H), 2.30 (s, 3H), 2.20 (t, 2H), 2.12 (d, 2H), 1.59 (m, 2H) 504 II- 96 y 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (3-pyrrolidin1 -yl-propyl) benzamide 0.15 4 as in example II 84 (300 MHz, CD3OD) δ 8.18 (s, 1H), 7.98 (s, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.35 (m, 2H ), 7.12 (t, 1H), 6.75 (q, 1H), 3.44 (t, 2H), 2.55 (m, 6H), 1.88 (d, 3H), 1.80 (m, 6H), 532

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 97 3- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) ethoxy] -pyrazin2-yl} -N- (3-pyrrolidin- 1-yl-propyl) benzamide 035 4 as in example II 84 (300 MHz, CDCb) δ 8.38 (s, 1 H), 8.18 (s, 2H), 7.92 (m, 2H), 7.48 (t, 1H) 7.02 (m, 211 ) 6.78 (q, 1H), 4.96 (s, 2H), 3.72 (m, 2H), 3.18 (m, 2H), 2.83 (m, 2H), 2.22 (m, 2H), 2.08 (m, 4H), 1.83 (d, 3H) 1.70 (m, 2H), 516 II- 98 3- {5-amino-6- [1- (2chloro-3,6-difluorophenyl) ethoxy] -pyrazin2-yl} -N- (1-methylpyridin-4-yl) benzamide 0.21 4 as in example II 84 (300 MHz, CDCb) δ 8.20 (s, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.44 (t, 1H ) 7.01 (m, 2H), 6.78 (q, 1H), 6.20 (bd, 1H), 4.98 (s, 2H), 4.09 (m, 1H), 2.97 ( m, 2H), 2.39 (s, 3H), 2.29 (m, 2H), 2.12 (m, 2H), 1.90 (d, 3H), 1.79 (m, 2H), 502 II- 99 O çn A 3- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) ethoxy] -pyrazin2-yl} -N- (2-pyrrolidin1-yl-ethyl) -benzamide 0.18 4 as in example II 84 (300 MHz, CDCb) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.48 (t, 1H), 7.06 (bm, 1H), 6.96 (m, 2H), 6.75 (q, 1H), 5.08 (s, 2H), 3.68 (m, 2H), 2.88 (m, 2H), 2.68 (m, 4H), 1.86 (m, 7H), 502 II- 100 $$ 3- {5-amino-6- [1- (2-chloro-3,6-difluoro- phenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin- 4-yl-ethyl) -benzamide 0.31 4 as in example II 84 (300 MHz, CDCb) δ 8.17 (s, 1H), 8.08 (s, 1H), 7.88 (d, 1H) 7.68 (d 1H), 7.48 (t, 1H), 6.98 (m, 2H), 6.80 (bt, 1H), 6.74 (q, 1H), 5.02 (s, 2H), 3.76 (m, 4H), 3.68 (m, 2H), 2.68 (m, 2H), 2.58 (m, 4H), 1.85 (d, 3H), 518 II- 101 N- [2- (4-acetylpiperazin-1-yl) -ethyl] 3- {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} - benzamide 0.64 4 as in example II 84 (300 MHz, CDCb) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.86 (d, 1H), 7.68 (d, 1H), 7.40 (t, 1H ), 6.98 (m, 3H), 6.71 (q, 1H), 5.13 (s, 2H), 3.69 (m, 4H), 3.51 (m, 2H), 2.80 (m, 2H), 2.66 (m, 4H), 2.08 (s, 3H), 1.83 (d, 3H), 559

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 102 iPi ^ aX · F (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4-methyl piperazin-1 -II) methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.82 (m, 2H), 7.41 (t, 1H), 7.28 (m, 1H), 6.95 (m, 2H), 6.71 (q, 1H), 5.00 (s, 2H), 3.85 (m, 2H), 3.46 (m, 2H), 2.36 (m, 4H), 2.33 (s, 3H), 1.63 (d, 3H), 488 II- 103 çex Γ (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.80 (m, 2H), 7.41 (t, 1H) 7.29 (m, 1H), 6.95 (m, 2H), 6.69 (q, 1H), 4.97 (s, 2H), 4.72 (m, 1H), 3.83 (m, 1H), 2.81 (m, 7H), 1.83 (d, 3H), 2.10-1.70 (m, 8H), 542 II- 104 X + o-C (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((3R- 5S) -3,5-dimethylpiperazin-1 -II) methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.03 (s, 1H), 7.80 (m, 2H), 7.41 (t, 1H), 7.29 (m, 1H), 6.95 (m, 2H), 6.70 (q, 1H), 5.00 (s, 2H), 4.68 (m, 1H), 3.56 (m, 1H), 2.75 (m, 3H), 2.42 (m, 1H), 1.83 (d, 3H), 1.57 (m, 1H), 1.15 (m, 3H), 0.96 (m, 3H), 502 II- 105 (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1-II) methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.04 (s, 1H), 7.83 (m, 2H), 7.39 (m, 2H), 6.98 (m, 2H), 6.70 (q, 1H ), 5.00 (s, 2H), 4.47 (m, 1H), 3.50 (m, 2H), 3.00 (m, 5H), 2.30 (m, 3H), 2.00 (m, 5H), 1.83 (d, 3H), 1.53 (m, 1H), 542 II- 106 ipoO ^NK í A Çs »L, F (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((R) -3amino-pyrrolidin-1yl) -methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.83 (m, 2H), 7.40 (m, 2H), 6.98 (m, 2H), 6.70 (q, 1H), 4.98 (s, 2H), 3.75 (m, 4H), 3,613.15 (m, 1H), 2.15 (m, 1H), 1.85 (d, 3H), 1.95- 1.75 (m, 3H), 300

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 107 ΦΛ (3- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((S) -3amino-pyrrolidin-1yl) -methanone 4 as in example II 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.83 (m, 2H), 7.40 (m, 2H), 6.98 (m, 2H), 6.70 (q, 1H ), 4.98 (s, 2H), 3.75 (m, 4H), 3,613.15 (m, 1H), 2.15 (m, 1H), 1.85 (d, 3H), 1.95- 1.75 (m, 3H), 300 II- 108 O ^ ° H F »ftA ΓΤ ⁰ ' ^ΗΜ ι 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((R) -3amino-pyrrolidin-1yl) -methanone 3 as in example I- 211 406 II- 109 4- {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -N- (3-pyrrolidin1 -yl-propyl) benzamide 0.1 4 as in the example 11109 (300 MHz, CDCb) δ 5.28 (bm, 1H), 8.04 (m, 3H), 7.84 (d, 2H), 6.95 (m, 2H), 6.71 (q, 1H ), 5.03 (s, 2H), 3.85 (m, 2H), 3.72 (m, 2H), 3.18 (m, 2H), 2.82 (m, 2H), 2.25 (m, 4H), 2.08 (m, 2H), 1.87 (d, 3H), 516 llHO φΥ 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4-methylpiperazin-1 -II) methanone 0.16 4 as in the example 11109 (300 MHz, CDCb) δ 7.99 (s, 1H), 7.78 (d, 2H), 7.43 (d, 2H), 7.29 (m, 1H), 6.85 (t, 1H), 6.94 (q, 1H), 5.07 (s, 2H), 3.75 (m, 2H), 3.50 (m, 2H), 2.43 (m, 4H), 2.33 (s, 3H), 1.84 (d, 3H), 488 iiin 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4pyrrolidin-1 -IIpiperin-1 -II) methanone 0.17 4 as in the example 11109 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.81 (d, 2H), 7.40 (d, 2H), 6.99 (m, 2H), 6.71 (q, 1H), 5.02 (s, 2H), 4.64 (m, 1H), 3.85 (m, 1H), 2.99 (m, 2H), 2.67 (m, 4H), 2.38 (m, 1H), 1.80 (m, 9H), 1.62 (m, 2H), 542

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 112 "H, F 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((3R5S) -3,5-dimethylpiperazin-1 -II) methanone 0.19 4 as in the example 11109 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.81 (d, 2H), 7.38 (d, 2H), 6.99 (m, 2H), 6.71 (q, 1H), 4.99 (s, 2H), 4.65 (m, 1H), 3.65 (m, 1H), 2.88 (m, 2H), 2.68 (m, 1H), 2.41 (m, 1H), 1.84 (d, 3H), 1.64 (m, 1H), 1.18 (s, 3H), 1.06 (s, 3H), 502 II- 113 (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.18 4 as in the example 11109 (300 MHz, CDCb) δ 8.07 (s, 1H), 7.81 (d, 2H), 7.53 (d, 2H), 6.95 (m, 2H), 6.69 (q, 1H), 4.99 (s, 2H), 4.45 (m, 1H), 3.55 (m, 2H), 2.95 (m, 4H), 1.902.3 (m, 9H), 1.82 (d, 3H), 1.65 (m, 1H), 542 II- 114 (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) - ((R) -2- pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.13 4 as in the example 11109 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.81 (d, 2H), 7.53 (d, 2H), 6.95 (m, 2H), 6.69 (q, 1H), 4.99 (s, 2H), 4.45 (m, 1H), 3.55 (m, 2H), 2.95 (m, 4H), 2.21 (m, 3H), 1.92 (m, 6H), 1.82 (d , 3H), 1.59 (m, 1H), 542 line 0 ^NH - 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((R) -3amino-pyrrolidin-1yl) -methanone 0.07 8 4 as in the example 11109 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.81 (d, 2H), 7.53 (d, 2H), 7.01 (m, 2H), 6.69 (q, 1H), 4.91 (s, 2H), 3.85 (m, 1H), 3.71 (m, 2H), 3.55 (m, 1H), 2.18 (m, 1H), 1.85 (d, 3H), 1.75 (m, 1H), 1.42 (m, 3H), 574 line A. kJk 4- {5-amino-6- [1- (2chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -N- (1-methylpiperidin-4-yl) benzamide 0.19 4 as in the example 11109 (300 MHz, CDCb) δ 8.06 (s, 1H), 7.82 (m, 4H), 7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s 2H), 4.09 (m, 1H), 2.97 (m, 2H), 2.39 (s, 3H), 2.29 (m, 2H), 2.12 (m, 2H), 1.90 (d, 3H), 1.79 (m, 2H), 502

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 117 O F 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-pyrrolidin1-yl-ethyl) -benzamide 0.11 4 as in the example 11109 (300 MHz, CDCb) δ 8.06 (s, 1H), 7.82 (m, 4H), 7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s, 2H ), 3.68 (m, 2H), 2.88 (m, 2H), 2.68 (m, 4H), 1.86 (m, 7H), 502 line χ-Ό ΦΑ 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin4-yl-ethyl) -benzamide 0.26 4 as in the example 11109 (300 MHz, CDCb) δ 8.06 (s, 1H), 7.82 (m, 4H), 7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s, 2H ), 3.75 (m, 4H), 3.56 (m, 2H), 2.62 (t, 2H), 2.52 (m, 4H), 1.83 (d, 3H), 518 II- 119 ΦΑ N- [2- (4-acetylpiperazin-1-yl) -ethyl] 4- {5-amino-6- [1- (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} - benzamide 0.48 4 as in the example 11109 (300 MHz, CDCb) δ 8.08 (s, 1 H), 7.82 (m, 4H), 7.00 (m, 2H), 6.70 (m, 2H), 5.03 (s, 2H), 3.62 (m, 4H), 3.50 (m, 2H), 2.65 (t, 2H), 2.52 (m, 4H), 2.10 (s, 3H), 1.83 (d, 3H), 559 II- 120 S '* ¹ ''CH ΦΛ 2- [4- (2-hydroxy-acetyl) piperazin-1 -II] ethanesulfonic acid (4 {5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.19 3 as in example I- 243 (300 MHz, CDCb) δ 7.96 (s, 1H), 7.75 (d, 2H), 7.24 (m, 3H), 7.08 (m, 1H), 6.95 (m, 1H ), 6.70 (q, 1H), 5.02 (s, 2H), 4.14 (s, 2H), 3.64 (m, 3H), 3.25 (m, 4H), 2.91 (m, 2H), 2.44 (m, 4H), 1.83 (d, 3H), 611 II- 121 ÇJ YCF. F 3- [5-amino6- (3-fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -benzoic acid 3 as in example I- 211 408 II- 122 O ^ o P 3- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.19 4 as in example II- 122 (300 MHz, CDCb) δ 8.09 (s, 1H), 7.88 (m, 2H), 7.56 (m, 1H), 7.44 (t, 1H), 7.34 (d, 1H), 7.21 (t, 1H), 5.69 (s, 2H), 4.92 (s, 2H), 4.70 (m, 1H), 3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.65 (m, 4H), 2.28 (m, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, 2H), 544

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 123 çcrV 3- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -N- {2- [ethyl- (2methoxy-ethyl) -amino] ethyl} -benzamide 0.45 4 as in example II- 122 (300 MHz, CDCb) δ 8.34 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.68 (d, 1H), 7.53 (m, 1H ), 7.50 (t, 1H), 7.45 (d, 1H), 7.21 (t, 1H), 6.79 (bm, 1H), 5.72 (s, 2H), 4.92 (s, 2H), 3.72 (m, 4H), 3.61 (m, 2H), 2.66 (m, 2H), 2.55 (m, 4H), 520 II- 124 {3- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -phenyl} - (4-methylpiperazin-1 -II) methanone 0.23 4 as in example II- 122 (300 MHz, CDCb) δ 8.10 (s, 1H), 7.90 (m, 2H), 7.60-7.20 (m, 5H), 5.70 (s, 2H), 4.91 (s, 2H), 3.85 (m, 2H), 3.50 (m, 2H), 2.52 (m, 2H), 2.32 (m, 2H), 2.33 (s, 3H) , 490 II- 125 ÇrV 'o F 3- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -N- {3-pyrrolidin1 -yl-propyl) benzamide 0.22 4 as in example II- 122 (300 MHz, CDCb) δ 8.85 (bm, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.60 (d, 1H), 7.56 (m, 1H), 7.45 (m, 2H), 7.20 (t, 1H), 5.72 (s, 2H), 4.92 (s, 2H), 3.61 (m, 2H), 2.72 (m, 2H), 2.57 (m, 4H), 1, 82 (m, 2H), 1.76 (m, 4H), 518 II- 126 Nh, N- [2- (4-acetylpiperazin-1-yl) -ethyl] 3- [5-amino-6- [1- (2-chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -benzamide 0.65 4 as in example II- 122 (300 MHz, CDCb) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.99 (d, 1H), 7.67 (d, 1H), 7.58 (m, 1H ), 7.52 (t, 1H), 7.42 (d, 1H), 7.22 (t, 1H), 6.75 (bm, 1H), 5.72 (s, 2H), 4.95 (s, 2H), 3.62 (m, 4H), 3.47 (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H), 2.08 (s, 3H), 561

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 127 0 ÇQY F {4- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -phenyl} - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.04 7 4 as in example II- 94 (300 MHz, CDCb) δ 8.10 (s, 1H), 7.88 (d, 2H), 1H), 7.52 (m, 1H), 7.44 (d, 2H), 7.42 (m, 1H), 7.20 (t, 1H), 5.71 (s, 2H), 5.05 (s, 2H), 4.62 (m, 1H), 3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.65 (m, 4H), 2, 28 (m, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, 2H), 544 II- 128 X Y * CF, {4- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -phenyl} - (4-methylpiperazin-1 -II) methanone 0.15 4 as in example II- 94 (300 MHz, CDCb) δ 8.08 (s, 1H), 7.88 (d, 2H), 7.55-7.40 (m, 4H), 7.21 (t, 1H), 5.72 s, 2H), 5.01 (s, 2H), 3.82 (m, 2H), 3.50 (m, 2H), 2.50 (m, 2H), 2.32 (m, 2H), 2.33 (s, 3H), 490 II- 129 ? yO F {4- [5-amino-6- (3fluor-2trifluoromethylbenciloxy) -pyrazin2-yl] -phenyl} - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1-II) methanone 0.05 2 4 as in example II- 94 (300 MHz, CDCb) δ 8.11 (s, 1H), 7.88 (d, 2H), 7.68 (m, 3H), 7.42 (d, 1H), 7.22 (t, 1H), 5.72 (m, 2H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), 1.84 (d, 3H), 1.57-2.18 (m, 11H), 544 II- 130 0¼ (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4-methylpiperazin-1 -II) methanone 0.17 4 as in example II- 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.79 (m, 2H), 7.40 (t, 1H), 7.29 (m, 1H), 7.01 (t, 1H), 6.81 (q, 1H), 5.06 (s, 2H), 3.85 (m, 2H), 3.46 (m, 2H), 2.51 (m, 2H), 2.35 (m, 2H), 2.33 (s, 3H), 1.84 (d, 3H), 506 II- 131 ÇT Çí LA _to NH, (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((3R, 5R) -3,5-dimethylpiperazin-1 - II) methanone 0.12 4 as in example II- 84 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.78 (m, 2H), 7.39 (t, 1H), 7.24 (m, 1H), 7.01 (t, 1H), 6.81 (q, 1H), 5.07 (s, 2H), 4.71 (m, 1H), 3.58 (m, 1H), 2.96 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.42 (m, 1H), 1.84 (d, 3H), 1.74 (m, 1H), 1.22 (d, 3H), 1.00 (d, 3H), 518

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 132 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (1-methylpiperidin-4-yl) benzamide 0.13 4 as in example II- 84 (300 MHz, CDCb) δ 8.16 (s, 1H), 7.99 (s, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.42 (m, 2H ), 7.15 (t, 1H), 6.74 (q, 1H), 3.95 (m, 1H), 2.98 (m, 2H), 2.34 (s, 3H), 2.25 (m, 2H), 2.01 (m, 2H), 1.84 (d, 3H), 1.73 (m, 2H), 520 II- 133 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-pyrrolidin1-yl-ethyl) -benzamide 0.17 4 as in example II- 84 (300 MHz, CDCb) δ 8.17 (s, 1H), 7.99 (s, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.38 (m, 2H) 7.12 (t, 1H), 6.72 (q, 1H), 3.64 (m, 2H), 2.86 (m, 2H), 2.75 (m, 4H), 2.25 (m, 2H), 2.01 (m, 2H), 1.84 (m, 7H), 520 II- 134 ,, ο ’ΛΑ 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin4-yl-ethyl) -benzamide 0.21 4 as in example II- 84 (300 MHz, CDCb) δ 8.13 (s, 1H), 8.03 (s, 1H), 7.85 (d, 1H), 7.67 (d, 1H), 7.42 (t, 1H ), 7.28 (dd, 1H), 7.00 (t, 1H), 6.86 (q, 1H), 6.84 (bm, 1H), 5.11 (s, 2H), 3.72 (m, 4H), 3.61 (m, 2H), 2.63 (m, 2H), 2.53 (m, 4H), 1.84 (d, 3H), 534 II- 135 THE 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (3-morpholin4-yl-propyl) benzamide 0.26 4 as in example II- 84 (300 MHz, CDCb) δ 8.19 (s, 1H), 8.06 (s, 1H), 7.87 (d, 1H), 7.70 (bm, 1H), 7.67 (d, 1H), 7.42 (t, 1H), 7.28 (dd, 1H), 7.01 (t, 1H), 6.86 (q, 1H), 5.11 (s, 2H), 3.64 (m, 6H), 2.54 (m, 2H), 2.48 (m, 4H), 1.84 (m, 5H), 548 II- 136 (3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4- cyclopropylaminopiperidin-1 -II) methanone 0.15 4 as in example II- 84 544

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 137 çAnro 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N - ((S) -2hydroxy-3-morpholin4-yl-propyl) benzamide 0.3 4 as in example II- 84 564 II- 138 Qor ΑΆ '* · » 3- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N - ((R) -2hydroxy-3-pyrrolidin1 -yl-propyl) benzamide 0.13 4 as in example II- 84 548 II- 139 (3- {6-amino-5- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyridin3-yl} -phenyl) - (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.07 1 4 as in example II- 84 (300 MHz, CDCb) δ 7.76 (s, 1H), 7.41 (m, 3H), 7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, 1H), 4.95 (s, 2H), 4.70 (m, 1H), 3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.65 (m, 4H), 2.28 (m, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, 2H), 559 II- 140 l »s 2diethylaminoethanesulfonic acid (4- {5 amino-6- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.35 3 as in example I- 243 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.70 (d, 2H), 7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, 1H), 6.82 (q, 1H), 5.05 (s, 2H), 3.22 (m, 2H), 3.00 (m, 2H), 2.55 (m, 4H), 1.83 (d, 3H), 1.60 (d, 6H), 556 II- 141 2- (4-hydroxypiperidin-1 -II) ethanesulfonic acid (4 {5-amino-6- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.21 3 as in example I- 243 (300 MHz, CDCb) δ 7.95 (s, 1H), 7.71 (d, 2H), 7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, 1H), 6.82 (q, 1H), 5.00 (s, 2H), 3.78 (m, 1H), 3.25 (t, 2H), 2.90 (t, 2H), 2.82 (m, 2H), 2.25 (m , 2H), 1.90 (m, 2H), 1.84 (d, 3H), 1.60 (m, 2H), 584

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 142 2diethylaminoethanesulfonic acid (4- {5 amino-6- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.22 3 as in example I- 243 (300 MHz, CDCb) δ 7.89 (s, 1H), 7.70 (d, 2H), 7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, 1H), 6.82 (q, 1H), 5.05 (s, 2H), 3.20 (m, 2H), 2.85 (m, 2H), 2.28 (s, 3H), 1.83 (d, 3H), 528 II- 143 2 - ((R) -3hydroxy-pyrrolidin-1 II) - ethanesulfonic acid (4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl ) -amide 0.19 3 as in example I- 243 (300 MHz, CDCb) δ 7.93 (s, 1H), 7.69 (d, 2H), 7.27 (m, 4H), 7.00 (t, 1H), 6.84 (q, 1H ), 5.03 (s, 2H), 4.43 (m, 1H), 3.25 (m, 2H), 3.02 (m, 3H), 2.84 (m, 1H), 2.53 (m, 1H), 2.30 (m, 1H), 2.22 (m, 1H), 1.84 (d, 3H), 1.81 (m, 1H), 570 II- 144 2-pyrrolidin- acid 1-yl-ethanesulfonic (4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin- 2-yl} -phenyl) -amide 0.36 3 as in example I- 243 (300 MHz, CDCb) δ 7.94 (s, 1H), 7.69 (d, 2H), 7.27 (m, 2H), 7.19 (d, 2H), 7.04 (t, 1H), 6.82 (q, 1H), 5.01 (s, 2H), 3.28 (m, 2H), 3.08 (m, 2H), 2.60 (m, 4H), 1.88 (m, 7H), 554 II- 145 CK, CH 0 ϊαΛ ÇÇ Th, 4- {5-amino6- [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) benzoic acid 1.56 3 as in example I- 211 422 II- 146 γΛ £> Xrf * TFA φφ ««, 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N - ((R) -2hydroxy-3-pyrrolidin1 -yl-propyl) benzamide 0.15 4 as in example II- 146 548 II- 147 ÂAAf “ 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4cyclopropylaminopiperidin-1 -II) methanone 0.13 4 as in example II- 146 544

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 148 yXO r 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} - N - ((S) -2hydroxy-3-pyrrolidin1 -yl-propyl) benzamide 0.12 4 as in example II- 146 548 II- 149 ΑΑοΧλ »Çk _and Íh, 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N - ((R) -2hydroxy-3-pyrrolidin1 -yl-propyl) benzamide 0.13 4 as in example II- 146 564 II- 150 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (1-methylpiperidin-4-yl) benzamide 0.06 8 4 as in example II- 146 (300 MHz, CDCb) δ 8.01 (s, 1H), 7.78 (m, 4H), 7.28 (m, 1H), 6.95 (t, 1H), 6.80 (q, 1H), 5.95 (bd, 1H), 5.07 (s, 2H), 4.05 (m, 1H), 2.85 (m, 2H), 2.32 (s, 3H), 2.21 (m, 2H), 2.08 (m, 2H), 1.85 (d, 3H), 1.68 (m, 2H), 518 II- 151 ? ΎΥ 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.18 4 as in example II- 146 (300 MHz, CDCb) δ 8.00 (d, 1H), 7.75 (d, 2H), 7.51 (d, 2R), 7.28 (m, 1H), 7.00 (t, 1H), 6.90 (q, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, 10H) 558 II- 152 _χ σ ° 0 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl (4pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.11 4 as in example II- 146 (300 MHz, CDCb) δ 7.00 (s, 1H), 7.75 (d, 2H), 7.40 (d, 2H), 7.28 (m, 1H), 6.99 (t, 1H), 5.76 (q, 1H) 5.04 (s, 2H), 4.64 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.60 (m, 4H), 2.30 (m, 1H), 1.92 (m, 1H), 1.81 (m, 6H), 1.69 (m, 2H), 1.62 (m, 2H), 558

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 153 ϋύ 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin4-yl-ethyl) -benzamide 0.10 2 4 as in example II- 146 (300 MHz, CDCb) δ 8.05 (s, 1H), 7.79 (m, 5H), 7.25 (m, 1H), 6.95 (t, 1H), 6.83 (q, 1H), 5.10 (s, 2H), 3.74 (m, 4H), 3.49 (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H), 1.85 (d, 3H), 536 II- 154 X ^to hh, 4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - (4-methylpiperazin-1 -II) methanone 0.16 4 as in example II- 146 (300 MHz, CDCb) δ 7.99 (s, 1H), 7.78 (d, 2H), 7.43 (d, 2H), 7.29 (m, 1H), 6.85 (t, 1H), 6.94 (q, 1H), 5.07 (s, 2H), 3.75 (m, 2H), 3.50 (m, 2H), 2.43 (m, 4H), 2.33 (s, 3H), 1.84 (d, 3H), 506 II- 155 0 ’Ύγ 4- {5-amino-6- [1- (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) - ((3R, 5S) -3,5-dimethylpiperazin-1 -II) methanone 0.09 5 4 as in example II- 146 (300 MHz, CDCb) δ 8.02 (s, 1H), 7.79 (d, 2H), 7.40 (d, 2H), 7.28 (m, 1H), 6.98 (t, 1H), 6.84 (q, 1H), 5.04 (s, 2H), 4.65 (m, 1H), 3.56 (m, 1H), 2.85 (m, 2H), 2.70 (m, 1H), 2.44 (m, 1H), 1.84 (d, 3H), 1.65 (m, 1H), 1.13 (m, 3H), 1.00 (m, 3H), 518 II- 156 0 look 4- {5-amino- 6- [1- (2,6-dichloro-3fluor-phenyl) -ethoxy] pyrazin-2-yl} benzoic 3 as in example I- 211 404 II- 157 | Αγ ^Α, 0 ^Ζ γ ^Ν 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - (4-pyrrolidin1 -yl-piperidin-1 -II) methanone 0.16 4 as in example II- 157 (300 MHz, CDCb) δ 8.05 (s, 1H), 7.82 (d, 2H), 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H ), 6.90 (q, 1H), 5.05 (s, 2H), 2.98 (br, 2H), 2.60 (s, 4H), 2.25 (br, 2H), 1.89 (d, 3H), 1,2- 1.98 (br, 8H), 540

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 158 To ά / ΐ 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.32 4 as in example II- 157 (300 MHz, CDCb) δ 8.16 (s, 1H), 7.89 (d, 2H), 7.75 (d, 2H), 7.32 (m, 2H), 7.15 (t, 1H), 6.91 (q, 1H), 6.78 (m, 1H), 5.10 (s, 2H), 3.74 (m, 4H), 3.63 (m, 2H), 2.65 (m, 2H), 2.54 (m, 4H), 1.85 (d, 3H), 516 II- 159 XhH 0 ÂAA Ά H. 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((3R, 5S) 3,5-dimethylpiperazin-1 -II) methanone 0.14 4 as in example II- 157 (300 MHz, CDCb) δ 8.05 (s, 1H), 7.82 (d, 2H), 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H ), 6.90 (q, 1H), 5.05 (s, 2H), 4.60 (s, 1H), 4.30 (t, 1H), 3.60 (s, 1H), 2.70 (m, 4H), 1.89 (d, 3H), 0.8- 1.2 (br, 6H), 500 II- 160 THE O 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} - N- (1-methylpiperidin-4-yl) benzamide 0.12 4 as in example II- 157 (300 MHz, CDCb) δ 8.16 (s, 1H), 7.90 (d, 2H), 7.83 (d, 2H), 7.32 (t, 2H), 7.16 (t, 1H ), 6.84 (q, 1H), 6.00 (d, 1H), 5.08 (s, 2H), 4.05 (m, 1H), 2.81 (m, 2H), 2.35 (s, 3H), 2.21 (m, 2H), 2.08 (m, 2H), 1.84 (d, 3H), 1.60 (m, 2H), 500 II- 161 (4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((R) -2pyrrolidin-1-ylmethylpyrrolidin-1-II) methanone 0.16 4 as in example II- 157 (300 MHz, CDCb) δ 8.05 (s, 1H), 7.82 (d, 2H), 7.50 (d, 2H), 7.26 (d, 2H) 7.15 (t, 1H) , 6.90 (q, 1H), 5.05 (s, 2H), 4.30 (t, 1H), 3.50 (m, 2H), 2.65 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, 10H) 542 II- 162 5? 0 AA (4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1-II) methanone 0.14 4 as in example II- 157 (300 MHz, CDCb) δ 8.05 (s, 1H), 7.82 (d, 2H), 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H ), 6.90 (q, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.86 (d, 3H), 1.70- 2.0 (m, 10H) 542

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 163 0 look (4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - (4-methylpiperazin-1 -II) methanone 0.15 4 as in example II- 157 (300 MHz, CDCb) δ 8.05 (s, 1 H), 7.82 (d, 2H), 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 6.90 (q, 1H), 5.05 (s, 2H), 3.60 (m, 4H), 2.45 (m, 4H), 2.31 (s, 3H), 1.89 (d, 3H) 486 II- 164 HH, (4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((R) -3aminopyrrolidin-1yl) -methanone 0.15 4 as in example II- 157 (300 MHz, CD3OD) δ 7.89 (m, 3H), 7.60 (m, 2H), 7.40 (m, 2H), 7.25 (m, 1H), 6.74 (m, 1H ), 4.90 (s, 2H), 4.05-3.60 (m, 4H), 3.50 (m, 2H), 2.50 (m, 1H), 2.18 (m, 1H) , 1.90 (d, 3H), 472 II- 165 «A y» -0 T όάΎ Hydrochloric salt (4 {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) ((S) -3-aminopyrrolidin-1 -II) methanone 0.1 4 as in example II- 157 (300MHZ, CD3OD) δ 7.89 (m, 3h), 7.60 (m, 2H), 7.40 (m, 2H), 7.25 (m, 1H), 6.74 (m, 1H) , 4.90 (s, 2H), 4.05-3.60 (m, 4H), 3.50 (m, 2H), 2.50 (m, 1H), 2.18 (m, 1H), 1.90 (d, 3H), 472 II- 166 O 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.11 4 as in example II- 157 (300 MHz, CDCb) δ 8.01 (s, 1H), 7.80 (m, 4H), 7.31 (dt, 2H), 7.16 (t, 1H), 6.84 (m, 2H), 5.04 (s, 2H), 3.55 (m, 2H), 2.71 (m, 2H), 2.57 (m, 4H), 1.84 (d, 3H), 1.83 (m, 4H), 502 II- 167 ÂA ° X M-c, «. 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (3-pyrrolidin-1 -IIpropyl) -benzamide 0.22 4 as in example II- 157 (300 MHz, CDCb) δ 8.80 (s, 1H), 8.10 (s, 1H), 7.80 (m, 4H), 7.21 (d, 2H), 7.16 (t, 1H), 6.84 (q, 1H), 5.04 (s, 2H), 3.55 (m, 2H), 2.71 (m, 2H), 2.57 (m, 4H), 1.84 (m, 4H), 1.83 (d, 3H), 1.81 (m, 2H), 514 II- 168 iT * ⁸ ! ^0H AW QA _c; 3- {5-amino- 6- [1- (2,6-dichlorophenyl) -ethoxy] -pyrazin- 2-il} -benzoico 3 as in example I- 211 404

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 169 3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (1-methylpiperidin-4-yl) benzamide 0.18 4 as in example II- 169 (300 MHz, CDCb) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.88 (d, 1H), 7.70 (d, 1H), 7.42 (t, 1H ), 7.28 (d, 2H), 7.10 (t, 1H), 6.94 (q, 1H), 6.15 (bd, 1H), 5.08 (s, 2H), 4.05 (m, 1H), 2.91 (m, 2H), 2.35 (s, 3H), 2.21 (m, 2H) , 2.08 (m, 2H), 1.84 (d, 3H), 1.68 (m, 2H), 502 II- 170 ΙΑ _α 3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (2-pyrrolidin-1-IIethyl) -benzamide 0.33 4 as in example II- 169 (300 MHz, CDCb) δ 8.15 (s, 1 H), 8.02 (s, 1H), 7.85 (d, 1H), 7.71 (d, 1H) 7.40 (t, 1H ) 7.28 (d, 2H), 7.10 (m, 2H), 6.90 (q, 1H), 5.10 (s, 2H), 3.64 (m, 2H), 2.80 (m, 2H), 2.64 (m, 4H), 1.85 (m, 7H), 500 II- 171 άΑ (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((3R, 5R) 3,5-dimethylpiperazin-1 -II) methanone 0.36 4 as in example II- 169 (300 MHz, CDCb) δ 8.04 (s, 1H), 7.79 (m, 2H), 7.40 (t, 1H), 7.28 (m, 3H), 7.11 (t, 1H), 6.86 (q, 1H), 5.05 (s, 2H), 4.69 (m, 1H), 3.56 (m, 1H), 2.95 (m, 1H), 2.79 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 1.84 (d, 3H), 1.25 (d, 3H), 1.17 (d, 3H), 500 II- 172 3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (2-morpholin-4-ylethyl) -benzamide 0.48 4 as in example II- 169 (300 MHz, CDCb) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.28 (d, 2H), 7.10 (t, 1H), 6.91 (q, 1H), 6.88 (m, 1H), 5.10 (s, 2H), 3.74 (m, 4H), 3.63 (m, 2H), 2.65 (m, 2H), 2.54 (m, 4H), 1.85 (d, 3H), 516 II- 173 (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((S) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.18 4 as in example II- 169 (300 MHz, CDCb) δ 8.01 (d, 1H), 7.87 (m, 2H), 7.37 (m, 2H), 7.28 (m, 2H), 7.11 (t, 1H ), 6.90 (m, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.84 (d, 3H), 1, 70-2.0 (m, 10H) 540

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Table 4 No. Structure Name MET IC50 (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 174 (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - (4-pyrrolidin1 -yl-piperidin-1 -II) methanone 0.17 4 as in example II- 169 (300 MHz, CDCb) δ 7.99 (s, 1H), 7.78 (m, 2H), 7.39 (t, 1H), 7.28 (m, 3H), 7.08 (t, 1H), 6.87 (q, 1H), 5.04 (s, 2H), 4.64 (m, 1H), 3.84 (m, 1H), 3.02 (m, 2H), 2.60 (m, 4H), 2.30 (m, 1H), 1.92 (m, 1H), 1.81 (m, 6H), 1.69 (m, 2H), 1.62 (m, 2H), 540 II- 175 N- [2- (4-acetylpiperazin-1-yl) -ethyl] 4- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} benzamide 0.28 4 as in example II- 169 (300 MHz, CDCb) δ 8.06 (s, 1H), 7.89 (d, 2H), 7.75 (d, 2H), 7.31 (dt, 2H), 7.11 (t, 1H), 6.91 (q, 1H), 6.78 (m, 1H), 5.12 (s, 2H), 4.25 (t, 1H), 3.60 (m, 3H), 3.45 (m, 1H), 2.65 (t , 2H), 2.50 (m, 3H), 2.05 (s, 2H), 1.85 (d, 3H), 559 II- 176 N- [2- (4-acetylpiperazin-1-yl) -ethyl] 3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} benzamide 0.35 4 as in example II- 169 (300 MHz, CDCb) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.99 (d, 1H), 7.69 (d, 1H), 7.43 (t, 1H ), 7.28 (d, 2H), 7.11 (t, 1H), 6.91 (q, 1H), 6.78 (m, 1H), 5.12 (s, 2H), 3.65 (m, 4H), 3.49 (m, 2H), 2.68 (m, 2H), 2.54 (m, 4H), 2.09 (s, 3H), 1.85 (d, 3H), 559 II- 177 (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((R) -2pyrrolidin-1-ylmethylpyrrolidin-1 -II) methanone 0.33 4 as in example II- 169 (300 MHz, CDCb) δ 8.01 (d, 1H), 7.87 (m, 2H), 7.37 (m, 2H), 7.28 (m, 2H), 7.11 (t, 1H ), 6.90 (m, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, 10H) 540

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 178 çMo R \ Λ _α 3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} N- (3-pyrrolidin-1 -IIpropyl) -benzamide 0.34 4 as in example II- 169 (300 MHz, CDCb) δ 8.48 (m, 1H), 8.22 (t, 1H), 8.05 (s, 1H), 7.91 (dt, 1H), 7.66 (d, 1H), 7.40 (t, 1H), 7.28 (d, 2H), 7.10 (t, 1H), 6.94 (q, 1H), 5.04 (s, 2H), 3.62 (m, 2H), 2.71 (m, 2H), 2.57 (m, 4H), 1.84 (d, 3H), 1.83 (m, 2H), 1.81 (m, 4H), 514 II- 179 (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - ((S) -3-aminopyrrolidin-1 -II) methanone 0.11 4 as in example II- 169 (300 MHz, CDsOD) δ 7.83 (m, 3H), 7.48 (m, 2H), 7.37 (m, 2H), 7.23 (m, 1H), 6.74 (m, 1H), 4.053.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H), 2.18 (m, 1H), 1.90 (d, 3H), 472 II- 180 HCl 0ΓΌ ·· ’· Hydrochloric salt (3 {5-amino-6- [1- (2,6dichloro-phenyl) -ethoxy] pyrazin-2-yl} -phenyl) ((R) -3-aminopyrrolidin-1 -II) methanone 0.18 4 as in example II- 169 (300 MHz, CDsOD) δ 7.83 (m, 3H), 7.48 (m, 2H), 7.37 (m, 2H), 7.23 (m, 1H), 6.74 (m, 1H), 4.053.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H), 2.18 (m, 1H), 1.90 (d, 3H), 472 II- 181 HQ o Or O (3- {5-amino-6- [1 (2,6-dichloro-phenyl) ethoxy] -pyrazin-2-yl} phenyl) - (4-methylpiperazin-1 -II) methanone 0.25 4 as in example II- 169 (300 MHz, CDCb) δ 8.00 (s, 1H), 7.80 (m, 2H), 7.40 (t, 1H), 7.28 (m, 3H), 7.11 (t, 1H), 6.87 (q, 1H), 5.05 (s, 2H), 4.64 (m, 1H), 3.87 (m, 2H), 3.45 (m, 2H), 2.53 (m, 2H), 2.36 (m, 1H), 2.34 (s, 3H), 1.84 (d, 3H), 486 II- 182 1- (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (2morpholin-4-yl-ethyl) urea 0.18 10 as in example I- 371 (300 MHz, CDCb) δ 7.93 (s, 1H), 7.68 (d, 2H), 7.38 (s, 2H), 6.95 (m, 4H), 6.70 (q, 1H), 4.94 (S, 2H), 3.75 (m, 4H), 3.46 (m, 2H), 2.69 (m, 4H), 2.26 (m, 2H), 1.85 (d, 3H), 534

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 183 0 P (R) -2pyrrolidin-1-ylmethylpyrrolidine-1 - carboxylic acid (4- {5 amino-6- [1- (2chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.21 10 as in example I- 371 (300 MHz, CDCb) δ 7.83 (s, 1H), 7.40 (d, 2H), 7.27 (d, 2H), 6.95 (m, 3H), 5.95 (q, 1H), 4.85 (s, 2H), 3.85 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.90 (m, 4H), 2.65 (m, 4H), 2.10 (m, 3H), 1.85 (d, 3H), 1.9-1.7 (m, 3H), 557 II- 184 0 1- (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (2pyrrolidin-1-yl-ethyl) urea 0.18 10 as in example I- 371 (300 MHz, CDCb) δ 7.91 (s, 1H), 7.80 (bs, 1H), 7.69 (d, 2H), 7.46 (d, 2H), 7.35 (bm, 1H), 7.05 (m, 2H), 6.72 (q, 1H), 4.86 (s, 2H), 3.58 (m, 2H), 3.19 (m, 4H), 3.12 (m, 2H), 2.16 (m, 4H), 2.51 (s, 3H), 1.81 (d, 3H), 517 II- 185 ΦΛ ¹ F 4-methylpiperazine-1-carboxylic acid (4- {5 amino-6- [1- (2chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.1 10 as in example I- 371 (300 MHz, CDCb) δ 7.95 (s, 1 H), 7.69 (d, 2H), 7.39 (d, 2H), 7.01-6.91 (m, 2H), 6.70 (m, 2H), 4.90 (s, 2H), 3.61 (m, 4H), 2.58 (m, 4H), 2.41 (s, 3H), 1.81 (d, 3H), 503 II- 186 ΦΛ 1- (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (2hydroxy-ethyl) -urea 0.21 10 as in example I- 371 (300 MHz, CDCb) δ 7.78 (s, 1H), 7.60 (d, 2H), 7.35 (d, 2H), 7.15 (m, 4H), 6.55 (q, 1H), 4.86 (s, 2H), 3.64 (t, 2H), 3.31 (t, 3H), 1.82 (d, 3H), 564 II- 187 0 zAzAyAi ** (S) -3-aminopyrrolidine-1 carboxylic acid (4- {5 amino-6- [1- (2chloro-3,6-difluorphenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.08 2 10 as in example I- 371 (300 MHz, CDCb) δ 7.71 (s, 1H), 7.65 (d, 2H), 7.53 (d, 2H), 7.15 (m, 3H), 6.77 (m, 1H ), 4.87 (s, 2H), 3.95 (m, 1H), 3.80 (m, 1H), 3.65 (m, 2H), 3.31 (m, 2H), 2.57 (m, 1H), 2.20 (m, 1H), 1.95 (d, 3H), 489 II- 188 φαΙϊ F 1- (4- {5-amino-6- [1 (2-chloro-3,6-difluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (1methyl-piperidin-4-yl) urea 0.05 4 10 as in example I- 371 517

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 189 hnXí · '' ^ THE. nn VA NR » 4-methylpiperazine-1-carboxylic acid (4- {5 amino-6- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 0.07 4 10 as in example I- 371 (300 MHz, CDCb) δ 7.94 (s, 1H), 7.66 (d, 2H), 7.37 (d, 2H), 7.24 (m, 1H), 6.95 (t, 1H), 6.81 (m, 2H), 4.95 (s, 2H), 3.68 (m, 4H), 2.73 (m, 4H), 2.51 (s, 3H), 1.83 (d, 3H), 519 II- 190 Λ- 0 γ 1- (4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (2hydroxy-ethyl) -urea 0.28 10 as in example I- 371 (300 MHz, CDCb) δ 7.84 (s, 1H), 7.60 (m, 4H), 7.33 (m, 3H), 7.15 (m, 1H), 6.70 (q, 1H), 4.86 (s, 2H), 3.64 (t, 2H), 3.31 (m, 3H), 1.82 (d, 3H), 480 II- 191 γΑ) - * J MCI (S) -3-aminopyrrolidine-1 carboxylic acid (4- {5 amino-6- [1- (2,6dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -amide 3 10 as in example I- 371 502 II- 192 1- (4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -phenyl) -3- (1methyl-piperidin-4-yl) urea 0.05 2 10 as in example I- 371 535 II- 193 THE 0 5- [5-amino6- [2-chloro-3,6difluoro-benciloxy) pyrazin-2-yl} thiophene-2-carboxylic acid 3 as in example I- 270 398 II- 194 0 χ F {5- [5-amino-6- [2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl} -thiophene-2-yl} (4-methyl-piperazin1-yl) -methanone 0.62 4 as in example II- 194 (300 MHz, CDCb) δ 8.01 (s, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 5.63 (s, 1H), 4.87 (m, 1H), 3.80 (m, 4H), 2.48 (m, 4H), 2.34 (s, 3H), 480

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 195 Λθ-0 * {5- [5-amino-6- [2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl} -thiophene-2-yl} (4-pyrrolidin-1 -IIpiperidin-1 -II) methanone 0.51 4 as in example II- 194 (300 MHz, CDCb) δ 8.01 (s, 1H), 7.35 (d, 1H), 7.24 (d, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 5.63 (s, 2H), 4.88 (m, 2H), 4.42 (m, 4H), 3.05 (t, 4H), 2.63 (m, 2H), 2.35 (m, 1H), 2.00 (m, 2H), 1.82 (m, 2H), 1.60 (m, 2H), 534 II- 196 Άα F {5- [5-amino-6- [2chloro-3,6-diflúorbenciloxy) -pyrazin2-yl} -thiophene-2-yl} ((3R-5S) -3,5dimethyl-piperazin-1yl) -methanone 0.55 4 as in example II- 194 (300 MHz, CDCb) δ 8.01 (s, 1H), 7.35 (d, 1H), 7.24 (d, 1H), 7.07 (m, 1H), 7.01 (m, 1H), 5.63 (s, 2H), 4.88 (m, 2H), 4.35 (m, 2H), 2.93 (m, 2H), 2.60 (m, 2H) 1.10 (d, 6H), 494 II- 197 ITC F {5- [5-amino-6- [2 chloro-3,6-diflúorbenciloxy) -pyrazin2-yl} -thiophene-2-yl} ((R) -2-pyrrolidin-1 ylmethyl-pyrrolidin-1 yl) -methanone 0.8 4 as in example II- 194 (300 MHz, CDCb) δ 8.03 (s, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 7.07 (m, 1H), 7.01 (m, 1H), 5.63 (s, 2H), 4.88 (m, 2H), 4.5- 0.80 (m, 17H) 534 II- 198 X {5- [5-amino6- [2-chloro-3,6difluoro-benciloxy) pyrazin-2-yl} thiophene-2-carboxylic acid (4morpholin-4-yl-ethyl) amide 0.7 4 as in example II- 194 (300 MHz, CDCb) δ 8.03 (s, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 7.20 (m, 1H), 7.05 (m, 1H), 6.58 (m, 1H), 5.65 (s, 2H), 4.89 (m, 2H) , 3.75 (m, 4H), 3.55 (m, 2H), 2.61 (m, 2H), 2.50 (m, 4H) 510 II- 199 Xi trifluoroacetate 3- [1- (2,6-dichloro-3fluor-phenyl) ethoxy] -5 {5 - [(4 methylpiperazin-1yl) carbonyl] pyridin-2yl} -pyrazin-2-amine 0.15 4 as in example II- 194 (DMSO-d6 + TFA / 300 MHz) δ 8.64 (s, 1H), 8.29 (s, 1H), 7.96 (d, 1H), 7.81 (d, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 6.63 (q, 1H), 4.69-4.25 (m, 1H), 4.08-3.69 (m, 1H), 3.58- 3.01 (m, 6H), 2.82 (s, 3H), 1.84 (d, 3H), 505 II- 200 1! ^ Α _α NH, C ^ »/ * ~ F OH 3- [1- (2,6-dichloro-3- fluorine-phenyl) -ethoxy] -5pyridin-4-yl-pyrazin2-ylamine 0.04 5 3 379

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 201 3- [1- (2,6-dichloro-3-fluoro-phenyl) -ethoxy] -5- (1 H-pyrrol-2-yl) pyrazin-2-ylamine 0.22 3 367 II- 202 O SHAH F OH (6- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-3-yl) - (4methyl-piperazin-1yl) -methanone 0.15 16 as in example I- 488 505 II- 203 (2- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-4-yl) - (4methyl-piperazin-1yl) -methanone 0.18 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 8.68 (d, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.52-7.27 (m, 3H), 6.57 (q, 1H ), 4.66 (m, 1H), 3.70-2.91 (m, 7H), 2.86 (s, 3H), 1.82 (d, 3H), 505 II- 204 (6- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-2-yl) - (4methyl-piperazin-1yl) -methanone 0.22 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 8.24 (s, 1H), 7.96 (dd, 1H), 7.79 (d, 1H), 7.53 (m, 2H), 7.35 (dd, 1H), 6.61 (q, 1H), 4.60 (br, 1H), 4.12 (br, 1H), 3.61 - 3.30 (m, 3H), 3.24- 3.04 (m, 3H), 2.83 (s, 3H), 1.84 (d, 3H), 505 II- 205 -0¾ LAs «η» (5- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-3-yl) - (4methyl-piperazin-1yl) -methanone 0.1 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.07 (s, 1H), 8.77 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.53 (br, 1H), 7.44 (m, 1H), 7.32 (m, 1H), 6.58 (q, 1H), 4.63 (br, 1H) , 3.74 (br, 1H), 3.61 - 3.15 (m, 4H), 3.06 (m, 2H), 2.83 (s, 3H), 1.81 (d, 3H), 505 II- 206 -0¾ \ Aq ** ”» (4- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-2-yl) - (4methyl-piperazin-1yl) -methanone 0.1 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 8.63 (d, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.43 (m, 1H), 7.28 (dd, 1H), 6.58 (q, 1H), 4.63 (m, 1H), 3.92 (m, 1H), 3.64-3.13 (m, 4H), 3.11 - 2.96 (m, 2H), 2.84 (s, 3H), 1.81 (d, 3H), 505

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Table 4 No. Structure Name MET ICso (μΜ) Procedure Ή-NMR MS m / z (M + 1) II- 207 «JTQ 'ÓA »·. 6- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin4-yl-ethyl) nicotinamide 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.76 (br, 1H), 8.96 (m, 2H), 8.37 (s, 1H), 8.26 (d, 1H), 7.80 (d, 1H), 7.51 (m, 1H), 7.37 (dd, 1H), 6.61 (q, 1H), 4.00 (d, 2H), 3.74-3.50 ( m, 6H), 3.34 (m, 2H), 3.16 (m, 2H), 1.83 (d, 3H), 535 II- 208 5- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (2-morpholin4-yl-ethyl) nicotinamide 0.03 8 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.16 (m, 1H), 9.09 (s, 1H), 9.03 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 7.47 (m, 1H), 7.32 (dd, 1H), 6.66 (q, 1H), 4.00 (d, 2H), 3.77-3.50 ( m, 6H), 3.35 (m, 2H), 3.16 (m, 2H), 1.83 (d, 3H), 535 II- 209 RO 6- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (3-morpholin4-yl-propyl) nicotinamide 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.74 (br, 1H), 8.97 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.26 (d, 1H), 7.79 (d, 1H), 7.50 (m, 1H), 7.37 (dd, 1H), 6.61 (q, 1H), 3.97 (d, 2H) , 3.64 (t, 2H), 3.50-3.30 (m, 4H), 3.23-2.98 (m, 4H), 1.92 (m, 2H), 1.83 (d , 3H), 549 II- 210 5- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -N- (3-morpholin4-yl-propyl) nicotinamide 0.02 2 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.88 (br, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 7.68-7.40 (m, 2H) , 7.32 (m, 1H), 6.67 (q, 1H), 3.97 (d, 2H), 3.66 (t, 2H), 3.43 (m, 4H), 3.25- 2.97 (m, 4H), 1.96 (br, 2H), 1.83 (d, 3H), 549

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Table 4 No. Structure Name MET ICso (μΜ) Procedure ¹ H-NMR MS m / z (M + 1) II- 211 "THE (6- {5-amino-6- [1 (2,6-dichloro-3-fluorophenyl) -ethoxy] -pyrazin2-yl} -pyridin-3-yl) - (4isopropyl-piperazin1-yl) -methanone 16 as in example I- 488 (DMSO-d6 + TFA / 300 MHz) δ 9.70 (br, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.53 (m, 1H) 7.39 (dd, 1H), 6.62 (q, 1H), 4.57 (br, 1H), 3.85 (br, 1H), 3.60-3, 05 (m, 7H), 1.83 (d, 3H), 1.26 (d, 6H), 533

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Table 5

Section A: Examples L-1 to L-16

Cl ⁰ ci-YUa ft Γ Htr ju ° Η, Ν-γ Ck ^ -CI Τ Ύ _F - * x ^ ft J iQr ° nr πχγ ^α _Ρ χφ ° ^ι aQi ° HjNyr ^ο ^ φ [' ^α % Inhibition = 58 % Inhibition = 59 % Inhibition = 63 % Inhibition = 47 Cr ° Cic ^ lyriy CkXLxi ft Cjj ⁰ Μ, Ν-γ ClCL-CI _f a> JDH HlC iQt ° ckJLxi _f a> HN ^ _Cr ⁰ CjA π, Ν-γ CKxLxi ΊΓ j % Inhibition = 68 % Inhibition = 69 % Inhibition = 66 % Inhibition = 72 CT ⁰ TjA HN -y ClCLxCI IJ Ω Htr Cl ⁰ H + i + r CI-sXLci IJ JU ⁰ Xja cCUci rft ° H.nA ’ % Inhibition = 64 % Inhibition = 67 % Inhibition = 67 % Inhibition = 82 / HIT Cr ⁰ rr ^H ₂ Nyr cu ^ Xyt _xja Η / ΐ'ητ CkftLxi 1 J ^ xr ° CI ^ A-Cl JL J γ HIT Cr ° Η, Ν ^ τ αγί, α ρΆ % Inhibition = 76 % Inhibition = 72 % Inhibition = 67 % Inhibition = 83

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Section B: Examples L-17 to L- 32

HhT ^ fl ⁰ Xj ^ «Xy CIxALci _f a> ΗΝ ^ θ Í1 ⁰ Xj ^ cAUci _f A> NH, Γτ * ° SjT ίΦτ ⁰ ΗΚγ ckJL, a Tj It ^0H HX * Η ^0, Ν'γ Oxx-Cl % Inhibition = 76 % Inhibition = 66 % Inhibition = 84 % Inhibition = 69 OyNH _z H * r Cr ⁰ Xj ^ cixJUci J j Q ° 'HljT rr ° ^H 2 ^N AC CIsAx-CI Τ Ύ HN ^ O * ⁰ ” ^HaN ò ^clv Ar ^a _f a ^ JlH Ci ⁰ CI.sxL.CI Y Ύ % Inhibition = 86 % Inhibition = 64 % Inhibition = 72 % Inhibition = 71 frog Η, νΑ ^ cixX ^ a ΤΎ X rr ° Xll ^ η, νΎ α ^ Χ ^ α 9 Cj ⁰ Xi axJAa XT ^{H (} V “'ΐ jpj ⁰ Κ, νΑχ cixAf ^a ρΛ ^ % Inhibition = 77 % Inhibition = 92 % Inhibition = 74 % Inhibition = 64 / Qr ⁰ XX ^ ^{η, ν} λ ^c SAr ^cl HhT Cr ^{0 h} í «T ^C, YY ^a _f A> <V ° ^H Ci ⁰ HjtAr CIxXxi _f a ^ Γ'Γ Ij ° 'ί'Φι ^ ^H = ^N αΑΓ, α JL J % Inhibition = 86 % Inhibition = 80 % Inhibition = 85 % Inhibition = 92

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Section C: Examples L- 33 to L- 48

Q Φ jíj ⁰ HjN'Sr cxXci jfj F -'- 'X' JC-Os. LJ HbT _u CT ⁰ JjK wry CIvAxCI Ij jXt ⁰ Ν · = ^ γΑ> □ xJUo II $, [QT ⁰ HjWyr ^α ΎΑ ^ΛΙ pAx % Inhibition = 63 % Inhibition = 62 % Inhibition = 55 % Inhibition = 62 rj ^{0 c} ^ P ^ [' ^a HhA φ jOr ° h ₂ n ' ^J V ^! CI- ^ xLa jfj ⁰ □ χΑ ,, α 1J ρ'ΧΧ % Inhibition = 75 % Inhibition = 86 % Inhibition = 77 % Inhibition = 55 7 Hj.N'S '' ⁵ oUL-ci • τΛ ⁰ ΐ * Ίι ^ ΗζΝ'ητ v ^c Ij ^{0 HíN} 6 A tY »f ^ f * ° πχψ ^ci Y ^ T ^jC1 % Inhibition = 84 % Inhibition = 55 % Inhibition = 85 % Inhibition = 55 jfjr ⁰ Η, Ν-'ηΤ ciyLci ρΛχ ¹ ç ç Pi ⁰ cixJUa HjtrSr rr ^ ClxJ ^ X! 1J _F x ^ % Inhibition = 84 % Inhibition = 78 % Inhibition = 83 % Inhibition = 67

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Section D: Examples L- 49 to L- 64

^ OH õ Η, Ν-'ν \.O 1J Hir JU ° Γϊ ^ HjfTY cisjLxi JL J ρ'ΧΖ The RR * ^0H ° HjnA <Ud Cl? J Αγ ^ ο fj * ⁰ XjY % Inhibition = 74 % Inhibition = 73 % Inhibition = 73 % Inhibition = 66 Η, ΚΤΥ cixJLLa rÃz z ΗΑΓ rr ⁰ Η, ΝγΤ ^α γ ^ ^α J γγ ^ ° 'ίΠι ¹ ' ^{5 ΗιΝ} ό ^c ^ P ^ ^ci HCL ^ Ij ° HjN'V ciAUci T j % Inhibition = 70 % Inhibition = 95 % Inhibition = 77 % Inhibition = 83 O HljT ° Η, Ν- ^ r ClxA ^ CI jQi Z 'A κ, κ'γ A hit (Ar ° Y ° CIxA ^ Cl HhT ⁰ Η, Ν'γ CIxX ^ CI IJ % Inhibition = 76 % Inhibition = 78 % Inhibition = 81 % Inhibition = 83 rj HhT Ϊ T Η, Ν'γ α · ^^, α .OH rjr ° ΓΓ ^ Η, ΓΤγ ckUUci 1 j up ** JLJ ⁰ KjN ^ Y α ^ Χχι trXX / HIT πχΥ ciUL-a _f A ^ % Inhibition = 71 % Inhibition = 94 % Inhibition = 58 % Inhibition = 85

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Section E: Examples L- 65 to L- 80

H / ry CkJLzCI Hhr JU ⁰ Η, ΝγΤ CI-yLci Γ ^ Ίί ⁰ fjT ^ H ₂ Ny X õ X laugh ⁰ ^ Y ^ ⁰¹ % Inhibition = 79 % Inhibition = 73 % Inhibition = 53 % Inhibition = 70 CT ⁰ d) ^ ^{H? 1} ò ciCUci ΙΖΓ - JU ⁰ nr ^ΗιΝ ό C ^ rUci hJ JU ⁰ Η, Υγ ^Ο ρτφ ^α % Inhibition = 66 % Inhibition = 71 % Inhibition = 92 % Inhibition = 62 jY ^{0 H, N} j ClxX-ΛΙ s Cl ⁰ dl ^ HjljY CkX-CI li J J? rr ° dr * ^ ClCUci IJ ^ι ι * ^ΐ * Ίι '^ Ck ^'Lz'CI eX ^ % Inhibition = 90 % Inhibition = 65 % Inhibition = 53 % Inhibition = 73 O JU ⁰ JTj H _s try c jTj ° Η, ΐΓγ cuJL, a Τ Ύ i Η & Γ ^HaN JÇ ck ^ Lo IJ pZ * S ^ J .AX % Inhibition = 54 % Inhibition = 68 % Inhibition = 73 % Inhibition = 60

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Section F: Examples L- 81 to L- 96

JU ⁰ umXLoH Η _ϊ Ν ' ^Λ γ α ^ Χ ^ α A Ρί ^{0 c} ^^ f ^cl ÇXdh Pt ⁰ CtxXxCl % Inhibition = 67 % Inhibition = 74 % Inhibition = 54 % Inhibition = 67 & ill ⁰ η, ν'Ύ CK / LxCI tf pA> Pjl ^ η ₂ ν ^ υ α ^ α ÍJ ⁰ Η / τ'γ CkUL-CI HN- ^ Pi ⁰ JCT ^ Ηχ * γ ci ^ JUa _f A> % Inhibition = 86 % Inhibition = 57 % Inhibition = 56 % Inhibition = 90 Έ pQT ⁰ Η, Νρτ OyLci 9 ⁰ Η, ^Ν> γ ClXUci HOyAj HljT H / I'S ' aULxCi Air ⁰ * ¹ JU ° HjTT CIsX ^ CI 1 J % Inhibition = 96 % Inhibition = 85 % Inhibition = 69 % Inhibition = 64 0 Hp PjT ^ ^HjN tT ^Ο ρΧ ^ ^α / Ρτ ⁰ H ₂ bTj CI ^ LzCI hX ° ^h I0I ⁰ CIvA-CI _F -O wr Xj ⁰ H ₂ N ^ y οι-Χ ^ οι % Inhibition = 62 % Inhibition = 51 % Inhibition = 65 % Inhibition = 61

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Section G: Examples L- 97 to L-112

_hi j - CoH ^ÍJ ° ^HiN i CI-ÃL-CI JM ! ^Η ΐ '^ ^ΌΗ Hty t ι ^ Ίτ ° iTi ^{0 0} rr ^ ϊΤι ’* Η, Ν'Ύ HjhTy HjirX οκΧ ^ οι I jT ciCC, ci ClxJL-CI 1 J 11 J % Inhibition = % Inhibition = % Inhibition = % Inhibition = 60 73 83 77 HO ^ x HljK O Χ ° ^Η HjT UF'CO ' JU ⁰ i T II J ^{h, r} a ΐΓΊι ^ Η, Ν'η '' ⁵ asJUci _f a ^ ciAÇci CKyX ^ CI α ^ Χ, α 1 J % Inhibition = % Inhibition = % Inhibition = % Inhibition = 79 82 91 89 1 ΟγΟ -OH % J Λ » HljT Q f ^{! f} ^ r ⁰ rp ° HN ^ jQj ⁰ Η, Ν-V ^HIN Ò n / Or ^cl YV ^Ci Cl JL.CI H.N-V _f a> Cixj ^ -Cl _f A ^ % Inhibition = % Inhibition = % Inhibition = % Inhibition = 81 89 87 70 fflA f ^s '' i ⁰ A ⁵ Y jQr ⁰ nr ^ «,« Ύ Η, Ν'ηΤ JL J jT J ClxJUci ciUL-α ^ vA ⁰¹ _f a> CtxJL-CI JT _F ^ v ^ % Inhibition = % Inhibition = % Inhibition = % Inhibition = 76 71 71 85

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Section H: Examples L-113 to L-128

pu ηκγ ⁰ κ, Ν-γ IJ Çx ^ z nr ° Γΐι Π / Ι ^ Ύ CIvÀril fr Η, Ν'Υ οϋγοι y nr ° nr ^ Η, Ν ^ γ CkAzCI % Inhibition = 57 % Inhibition = 56 % Inhibition = 63 % Inhibition = 62 HnT iQT ° HjtAv CIvX ^ CI A r nr 0 nr ^ ^H a ^N l ^ χ_, 0 cixÁ ^ a _f a> ? fjr ° HjirY cPLai I j y íTí ⁰ ^ nr * ^ ^HjN to CIxAxi _F z <^ % Inhibition = 60 % Inhibition = 86 % Inhibition = 59 % Inhibition = 63 J η ₂ νΑ ^ ckAxi y hn ^ Qi ⁰ hjty ci, JLa tjt iQr ⁰ Η, Ν-γ ¹ CkJLzC! 1 J nr ° h ₃ m ^ Y CkA ^ C * 17 _f a ^ í % Inhibition = 75 % Inhibition = 61 % Inhibition = 80 % Inhibition = 69 'νΧ JU ⁰ ' ^ Ίι ^ h / cy Cl ^ zU-Ci 1T F ^^ Ψ ÍT ⁰ nl ^ ry CIxAlci 1 J ⁰ η, νΎ ^ caJLz-ci rA> ΗΝ'Ί '* jfjr ° cKxLzCi 1 j % Inhibition = 77 % Inhibition = 52 % Inhibition = 56 % Inhibition = 64

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Section I: Examples L-129 to L-144

iQr ° KjnAt OvAzCI η, νΎ χ.0 ciA ^ ci Tj ρ'ΧΛ ' hnAP fr ° HjN'S ' ^C ^ jAf ^CI iTj ⁰ Ηχγ αγΑχ: ι _f A> % Inhibition = 82 % Inhibition = 60 % Inhibition = 61 % Inhibition = 65 X ΗΚΓ p] ⁰ jpp ^ ClyLci $ ⁰ Η, Ν'γ □ sJUci p | ⁰ xJ αΧα Pi ^{0 c} sXr ^cl _f a> % Inhibition = 68 % Inhibition = 76 % Inhibition = 76 % Inhibition = 61 Ψ O ÍJ ° Η, Ν'ηΓ Clx ^ XxCI T j HtYrr ° Η, κΑχ α- ^ χ ^ α iQT ⁰ ΓΡ ^ Η, Ν ^ γ ClxJLxCI IJ haA Pp ⁰ ClxJU-O _f a> % Inhibition = 78 % Inhibition = 83 % Inhibition = 60 % Inhibition = 64 ΛΗ ó rbi ⁰ np Η, ΐ / γ ciyLa ρΛ ^ ϊΏι ^ κχγ ci-Aci Ηχγ CkXj2I I J X ^The HjNSr % Inhibition = 79 % Inhibition = 72 % Inhibition = 59 % Inhibition = 71

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Section J: Examples L-145 to L-160

1 cyo Ύ iQr ⁰ Η, Ν-γ OyL-a Xo 0 fAi ⁰ HjN-y ckAa ¹ _f A> ύ ç íCl ⁰ κκΑρ α ^ ζΧα fAX F-í-F hit ( ⁰ hX)! ClALxCI YJT % Inhibition = 77 % Inhibition = 89 % Inhibition = 96 % Inhibition = 62 yco Ύ (Tj * ⁰ 1X1 ^ v aULzO jT Ύ nsr CkJLzCI fax rCi ⁰ HjN ^ Sç Pu ζΧ'Ογ ^ χγΧ) Ηχητ CIxJLzCI _f a> % Inhibition = 70 % Inhibition = 81 % Inhibition = 58 % Inhibition = 53 Φ Pr ⁰ hXj CkA-CI IJ 2? HN ΓΓ ⁰ Xjj X A- rtr ¹ Xj ⁰ ν ^ 'Ίι ^ ciUCci Tjí xX ° Η, νΑτ ClyUa _F AA % Inhibition = 95 % Inhibition = 77 % Inhibition = 66 % Inhibition = 73 $ H / i'Sr CkJLzCI Ύ Ύ _F z * ^ JU ⁰ H ₂ nA <ciCLci TJT AJÕ HkT Xj ⁰ cixXxi IJ _F ^ Z · HjnX ^ ClCÇ-CI % Inhibition = 77 % Inhibition = 63 % Inhibition = 78 % Inhibition = 59

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Section K: Examples L-161 to L-176

Η, Ν-η-- I J So aJua 1 j 0 ^ = 0 ô ¥ Γ'ι ^{0 H} J ^N Ar CI ^ JUc! _f a> _h $ Lh JU ⁰ Ν ^βί γ ^ CKzLxi % Inhibition = 79 % Inhibition = 66 % Inhibition = 83 % Inhibition = 61 $ ^{0 h} ₂ N Sy cUL-ci IJ / ϊΓιι THE HtJ η, νΑ '* ClAci pAz y T AU ⁰ HjtrSy ΟΙχΧχ » % Inhibition = 88 % Inhibition = 67 % Inhibition = 66 % Inhibition = 90 HjN'Sr α ^ Χ, α jPj HhT Γ ^ Ίι ⁰ Xj axJLxi Q A [Ά [ ⁰ η, νΑτ CkA ^ CI 1 J Ta ⁰ HjtrSy cOUci _F Az % Inhibition = 79 % Inhibition = 77 % Inhibition = 69 % Inhibition = 79 iQT ⁰ Η, Ν'Υ ciUUci IJ ηνΆ ^ iQO * HjbTV CKsJUci jT j Ij ^ CI ^{6 0} CLXX Jí T oA k ϊΓΐι ^ ci ^ JUci Tj % Inhibition = 63 % Inhibition = 68 % Inhibition = 60 % Inhibition = 51

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Table 6

Section A: Examples L-177 to L-192

0 ΜγΟ OH % Inhibition = 26 % Inhibition = 30 % Inhibition = 24 % Inhibition = 26 OO? J0L α'Ύ ^ 'α XjL ·? ^ ° ^ sZ * ^í ? jO ¹ ύζ / Χ % Inhibition = 31 % Inhibition = 27 % Inhibition = 32 % Inhibition = 27 JÚL rL jOl O ^^ CHj jfjl oçr % Inhibition = 29 % Inhibition = 30 % Inhibition = 30 % Inhibition = 39 ί-ΧΊ, the X O ^^ CH, H.C-l-Oi, 0 ^ “· and jfji % Inhibition = 35 % Inhibition = 35 % Inhibition = 38 % Inhibition = 44

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Section B: Examples L-193 to L-208

? \ il 1 t J iTj O / X NHg % Inhibition = 37 % Inhibition = 35 % Inhibition = 37 % Inhibition = 34 Χχ, Ζ ⁸ 'rjr go- _The jÇjL _the ίΧ s XX XY % Inhibition = 36 % Inhibition = 59 % Inhibition = 33 % Inhibition = 31 look oct % Inhibition = 30 % Inhibition = 33 % Inhibition = 33 % Inhibition = 51 yCT HO ,. ÓÇ ° ^ J? jfjl 07 y X ^ jÒ ΓΤ T % Inhibition = 32 % Inhibition = 32 % Inhibition = 33 % Inhibition = 27

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Section C: Examples L-209 to L- 224

α'γτ! ιΐχ ftp 'XX / % Inhibition = 31 % Inhibition = 39 % Inhibition = 31 % Inhibition = 36 there is/* ΚΠ QCa J0L aCCi ^V Yil ftj * ⁰ % Inhibition = 31 % Inhibition = 49 % Inhibition = 33 % Inhibition = 29 η Y 0 «^ ά? Ύ % Inhibition = 34 % Inhibition = 35 % Inhibition = 34 % Inhibition = 32 jQl V cXÇb, Xju » J / '0 X % Inhibition = 29 % Inhibition = 26 % Inhibition = 29 % Inhibition = 30

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Section D: Examples L-225 to L-240

, 0. écV jTX bAa k jQl ^ Yi % Inhibition = 33 % Inhibition = 24 % Inhibition = 83 % Inhibition = 24 ÒCT The. JT / ^-08 ΗΓ ° θχΑζ ° Xj * % Inhibition = 24 % Inhibition = 23 % Inhibition = 62 % Inhibition = 44 W AA „jOO άΓ ^ * νγ ^ θ ^ΧθΜ 07? iLXu ^{, íh} * % Inhibition = 32 % Inhibition = 34 % Inhibition = 36 % Inhibition = 33 JL-JU ___ 0 (5 \ 2 ~ x THE % Inhibition = 30 % Inhibition = 35 % Inhibition = 34 % Inhibition = 30

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Section E: Examples L- 241 to L- 256

0ΟΎ XXxo Λ Ϊ jPii Π ° Ύ LitAu w » n-y ». γθ ÒXr % Inhibition = 30 % Inhibition = 66 % Inhibition = 32 % Inhibition = 33 F ι_Δ kA _o U j? ¹ u £ / X % Inhibition = 33 % Inhibition = 28 % Inhibition = 25 % Inhibition = 27 N ^ Ax. ^ 0 IL jfjL uU O "s Π % Inhibition = 32 % Inhibition = 37 % Inhibition = 29 % Inhibition = 32 KGyOS 0¾ ^ oc jQl Xa ^ o THE % Inhibition = 28 % Inhibition = 45 % Inhibition = 45 % Inhibition = 46

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Section F: Examples L- 257 to L- 272

Λ ⁰ Y ^N ' ^eH · CÇ, Ή CX % Inhibition = 43 % Inhibition = 45 % Inhibition = 39 % Inhibition = 40 7 NH £ Ck. % Inhibition = 40 % Inhibition = 42 % Inhibition = 36 % Inhibition = 38 ? % Αη. òo4 % Inhibition = 17 % Inhibition = 10 % Inhibition = - 5 % Inhibition = 15 (ΓΤ XI 9—0 “άχ Ή Ο y-ç V -> * s Η ^ ζ-Ν '“Ν % Inhibition = 10 % Inhibition = - 2 % Inhibition = 16 % Inhibition = 15

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Section G: Examples L- 273 to L- 288

XX OH) oc ΧΟΡΟ X % Inhibition = 17 % Inhibition = 19 % Inhibition = 28 % Inhibition = 32 h, <X ^^ jOl Χγ the < γ / J όθΎ % Inhibition = 26 % Inhibition = 31 % Inhibition = 32 % Inhibition = 56 k Ya PS àcV - / V-OÒ ' % Inhibition = 26 % Inhibition = 22 % Inhibition = 26 % Inhibition = 27 άΡ JXjL % Inhibition = 31 % Inhibition = 47 % Inhibition = 21 % Inhibition = 20

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Section H: Examples L- 289 to L-304

JuX LX _to X, α— lx> % Inhibition = 24 % Inhibition = 19 % Inhibition = 26 % Inhibition = 99 ôA OC jLj ^N A ^ xy- ° ¹ · _a jÇk _a I li ° * z * _ r ^ r ^H % Inhibition = 16 % Inhibition = 20 % Inhibition = 18 % Inhibition = 23 0 ^ 0 O7X α - '^ Α I © ^t oj ^ _t? jAil * % Inhibition = 26 % Inhibition = 31 % Inhibition = 25 % Inhibition = 22 OO? THE. -s. JL · Jn ίΥ »j ΌγΟ K % Inhibition = 24 % Inhibition = 41 % Inhibition = 24 % Inhibition = 18

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Section I: Examples L-305 to L-320

&? CÁ T The r ers jCOCu % Inhibition = 26 % Inhibition = 22 % Inhibition = 22 % Inhibition = 33 Ájl h.c- ^ 50 υψ M JLA Ό0 % Inhibition = 16 % Inhibition = 16 % Inhibition = 17 % Inhibition = 19 CX _O «. uCl tto CÁ k % Inhibition = 10 % Inhibition = 16 % Inhibition = 72 % Inhibition = 11 ^a > _s z''A-z ' ^a % Inhibition = 12 % Inhibition = 17 % Inhibition = 71 % Inhibition = 28

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Section J: Examples L- 321 to L- 336

α? χ jQl h ^ -UL Ν ^ χΧ ^ ® OH Ή ÇT % Inhibition = 25 % Inhibition = 25 % Inhibition = 26 % Inhibition = 25 0 try ^ a Vy CHiJ JlX, α % Inhibition = 26 % Inhibition = 3 % Inhibition = 26 % Inhibition = 27 ♦ Viy ^ X ^, y = f 0 yj o a J \ X J 0 % Inhibition = 30 % Inhibition = 74 % Inhibition = 23 % Inhibition = 21 cr ⁷ ° % Inhibition = 23 % Inhibition = 17 % Inhibition = 18 % Inhibition = 20

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Section K: Examples L- 337 to L- 352

X χχ % Inhibition = 20 % Inhibition = 21 % Inhibition = 18 % Inhibition = 19 (Y ^ T % Inhibition = 20 % Inhibition = 36 % Inhibition = 37 % Inhibition = 41 n—? The h — o ' % Inhibition = 45 % Inhibition = 31 % Inhibition = 38 % Inhibition = 35 XI α'γ'τι 1 HJ3 „ _ ΗΛΛ z ~ -, N ^ xk »A0 iL The ^ Ace. kP ^ ds % Inhibition = 32 % Inhibition = 34 % Inhibition = 35 % Inhibition = 47

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Table 7

Section A: Examples L- 353 to L- 368

f ^NH * F OylO ^ Γ w çA ^ n ifll % Inhibition = % Inhibition = % Inhibition = % Inhibition = 24 19 32 22 rr ° O ^ΝΗϊ f-5-f ^NHí F F % Inhibition = % Inhibition = % Inhibition = % Inhibition = 20 14 24 10 o ~ rkJ Q õ _H? yCrC ^nh = ° * N % Inhibition = 8 % Inhibition = 37 % Inhibition = 36 % Inhibition = 6 NH, Cl r MS F / -Ç % Inhibition = 8 % Inhibition = 9 % Inhibition = 6 % Inhibition = 27

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Section B: Examples L- 369 to L- 384

O ΟγΝχχΙ kXr oA. here Cl Y »s % Inhibition = 10 % Inhibition = 19 % Inhibition = 10 % Inhibition = 49 ΟψίΚχΙ '° ^ ^Λ ' ο AfNHi Cf «Η ⁸ Cl ΟγΧΐ O % Inhibition = 19 % Inhibition = 5 % Inhibition = 10 % Inhibition = 10 The ^ nCX ^ 0 at oA ¹ α THE nHj çXJn oc Y ^ CI Cl çV Cl % Inhibition = 19 % Inhibition = 34 % Inhibition = 40 % Inhibition = 26 ^c S ^tf? r OyJ or % Inhibition = 26 % Inhibition = 9 % Inhibition = 14 % Inhibition = 9

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Section C: Examples L- 385 to L- 400

ΟγΝ- ^ J ΜΗ, THE ΡΎ ^NH i, ξ ^NH ' % Inhibition = 10 % Inhibition = 13 % Inhibition = 8 % Inhibition = 24 <u2r ° Fj) OyH ^ J 0 çXJl Ύύ - IT * ^ ³ JL ^F % Inhibition = 14 % Inhibition = 15 % Inhibition = 15 % Inhibition = 28 V ⁴ NHj pAíAp Ζγζ: ^WHl F % Inhibition = 26 % Inhibition = 12 % Inhibition = 19 % Inhibition = 12 O ^ M ^ J 7 ’ F 0 NH _to F ÍJJ fV 0 ru ç / Jq PjX nh, % Inhibition = 30 % Inhibition = 10 % Inhibition = 28 % Inhibition = 21

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Section D: Examples L-400 to L-416

Γ X * NH _a oc o «| * o o CXr ² '* 0 NHj \ <N % Inhibition = 9 % Inhibition = 11 % Inhibition = 4 % Inhibition = 41 THE g ^F T ^F f JZJL ft ft ft ft % Inhibition = 21 % Inhibition = 14 % Inhibition = 13 % Inhibition = 12 WS O γ> ; γ ft / g % Inhibition = 31 % Inhibition = 19 % Inhibition = 27 % Inhibition = 25 A oftft 0 Br NH, ' B % Inhibition = 31 % Inhibition = 45 % Inhibition = 11 % Inhibition = 77

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Section E: Examples L- 417 to L- 432

JiH f Ογζ ^ V cXr ^D Γτ yNH ó % Inhibition = 11 % Inhibition = 9 % Inhibition = 12 % Inhibition = 7 0 ^ 0 ° rp Y çj- ^nh í jQ ΓΓ ^ΝΗϊ hAo % Inhibition = % Inhibition = % Inhibition = % Inhibition = 10 14 10 12 ίΆ OyNsJ MHj Π «Η, T * r ^{Í, JH1} NH, Jx oUUJ OyAj> and JNH <r % Inhibition = % Inhibition = % Inhibition = % Inhibition = 13 11 10 11 oXr ° The «Jv 0¾ ç/ O P % Inhibition = % Inhibition = % Inhibition = % Inhibition = 13 11 10 18

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Section F: Examples L- 433 to L- 448

^{W |} X ^ 7 A % Inhibition = 23 % Inhibition = 47 % Inhibition = 15 % Inhibition = 24 HlpO 6th «Cr ^F '/ TF ~ % Inhibition = 32 % Inhibition = 19 % Inhibition = 21 % Inhibition = 59 oXr ° HhAo tf ηλΑ Ψ õ % Inhibition = 20 % Inhibition = 26 % Inhibition = 24 % Inhibition = 26 pA A F -? - F F rP ΛζΡ® nh, ^ 7 °° % Inhibition = 21 % Inhibition = 16 % Inhibition = 14 % Inhibition = 15

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Section G: Examples L- 449 to L- 464

çXJl Ma p F O ^ N ^ J p C »N HO ^ % Inhibition = 15 % Inhibition = 17 % Inhibition = 12 % Inhibition = 15 0 0 y ³ THE -rsJí NHj 'S sr'Sr NHj f izj ώ Ojjjl H / 1% % Inhibition = % Inhibition = 13 % Inhibition = 13 % Inhibition = Γτ „(^ Ro-Q * Yo % Inhibition = 33 % Inhibition = 11 % Inhibition = 17 % Inhibition = 15 Γ pT NH _a p? % Inhibition = 31 % Inhibition = 23 % Inhibition = 22 % Inhibition = 12

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Section H: Examples L- 465 to L- 480

OyhkJ OyM ^ J r THE % Inhibition = 14 % Inhibition = 18 % Inhibition = 13 % Inhibition = 13 J Q O cdPH Χ> ό % Inhibition = 10 % Inhibition = 9 % Inhibition = 10 % Inhibition = 9 Al * ³ Λ shah F n % Inhibition = 50 % Inhibition = 39 % Inhibition = 51 % Inhibition = 27 or · O* % Inhibition = 29 % Inhibition = 24 % Inhibition = 15 % Inhibition = 17

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Section I: Examples L- 481 to L- 496

0 0 ^H A ^3_ Q cj '- / aJ % Inhibition = 16 % Inhibition = 20 % Inhibition = 19 % Inhibition = 16 -áêSy 7Ο-Ό g OyNs> α ο'η'Ν ZvN, ΗΛ TOO % Inhibition = 18 % Inhibition = 22 % Inhibition = 63 % Inhibition = 17 Γ PyJ NHj ^ 0 _AJi / f BAD X % Inhibition = 18 % Inhibition = 23 % Inhibition = 16 % Inhibition = 22 OyN ^ J The tf - ó Ç-Ç ¹ / · / λΑ -iC · % Inhibition = 14 % Inhibition = 18 % Inhibition = 14 % Inhibition = 14

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Section J: Examples L- 497 to L- 512

^F X_zs _r N HjN OylO * ¹ ^ cM % Inhibition = 34 % Inhibition = 24 % Inhibition = 19 % Inhibition = 19 X THE yoo ^Ck o5 ^ H> 0-0 % Inhibition = 18 % Inhibition = 19 % Inhibition = 17 % Inhibition = 16 / 00 To Shj x / K, n % Inhibition = 17 % Inhibition = 17 % Inhibition = 20 % Inhibition = 12 .'V'o-V * ^^ Φ-Ο-Ο % Inhibition = 16 % Inhibition = 23 % Inhibition = 16 % Inhibition = 16

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Section K: Examples L- 513 to L- 528

w ç/·* % Inhibition = 16 % Inhibition = 17 % Inhibition = 17 % Inhibition = 16 o A i-yO F THE You, f "Xj o-oc % Inhibition = 19 % Inhibition = 15 % Inhibition = 8 % Inhibition = 14 O ^ N ^ J CkJ NH _S Cl THE çALm MK. THE HH ₂ % Inhibition = 23 % Inhibition = 7 % Inhibition = 9 % Inhibition = 5 Jpi OC % Inhibition = 5 % Inhibition = 10 % Inhibition = 9 % Inhibition = 9

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Section L: Examples L- 1529 to L- 548

NyN rX C NH, OO ^ zOVx % Inhibition = 9 % Inhibition = 8 % Inhibition = 8 % Inhibition = 27 0 Ϋ jfi % Inhibition = 12 % Inhibition = 18 % Inhibition = 4 % Inhibition = 16 ΟγΝ · Χ λ Y cr * Xer % Inhibition = 12 % Inhibition = - 2 % Inhibition = 28 % Inhibition = 11 X OyJkJ J.N % Inhibition = 5 % Inhibition = 6 % Inhibition = 7 % Inhibition = 8 The «JkJ 0 K % Inhibition = 11 % Inhibition = 11 % Inhibition = 64 % Inhibition = 18

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Table 8

Section A: Examples L- 549 to L- 561

| AH Oft / x O Ah O ^^ N ^ At, O T ft NH 0 ^ xjj NHj % Inhibition = % Inhibition = % Inhibition = % Inhibition = 11 13 11 20 _the ft Ah OyN ^ k, Anh ΟγΝχΑ. 0 , Χ · r-y ™ » ft NH. | ΓΎ F % Inhibition = % Inhibition = % Inhibition = % Inhibition = 25 14 21 12 Ah O oft THE* ACI NH, RJ oft % Inhibition = % Inhibition = % Inhibition = % Inhibition = 40 27 32 16 CWíftx Ah ft NysN ° * ν / X F-f-F % Inhibition = % Inhibition = % Inhibition = 7 % Inhibition = 16 17 21

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Section B: Examples L- 565 to L- 580

Ah O Ά -A ’NHj cAr Cl THE at F ^ Y ^ F % Inhibition = 28 % Inhibition = 29 % Inhibition = 20 % Inhibition = 25 ⁰ ukz Aih Ah Ά O F oA ^ Air shah O % Inhibition = 22 % Inhibition = 41 % Inhibition = 28 % Inhibition = 17 THE ^H Ó ιΤι ^ ' ⁰ ''?) fALH OylKzk hello hà ^ J Fs / U NM- JJ 9-V % Inhibition = 19 % Inhibition = 33 % Inhibition = 11 % Inhibition = 24 F-4-F O ΟγΧχΑχ Anh ΟγΛχΑ. AAo jfY ^ bAA ^Bf ' ^s Çí ^ Br OvA % Inhibition = 24 % Inhibition = 29 % Inhibition = 42 % Inhibition = 73

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Section C: Examples L- 581 to L- 596

T Ah r ΐμ A ^H % Inhibition = 19 % Inhibition = 17 % Inhibition = 14 % Inhibition = 9 Aih ô Ah ώϋ F F-r \ / Cl Cl the ° % Inhibition = 30 % Inhibition = 6 % Inhibition = 26 % Inhibition = 32 Ah 0U <A. Amh 0 HERE THE· 0 HhAo 6 C ^ % Inhibition = % Inhibition = % Inhibition = % Inhibition = 15 18 18 19 Ah çjòí THE* Ah 0 <Akxk. çr ^NHi HlAo “Η, z ^ΜΗ ' % Inhibition = 12 % Inhibition = 10 % Inhibition = 8 % Inhibition = 19

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Section D: Examples L- 597 to L- 612

y X, XaA ⁵ wúJ * Vnh, « % Inhibition = 28 % Inhibition = 17 % Inhibition = 58 % Inhibition = 25 tf h-nAíL nr The F oAkSx T O 0 % Inhibition = 17 % Inhibition = 17 % Inhibition = 20 % Inhibition = 12 (The «IH OoAsAs. Aih o y THE* Ύ BrÍ % Inhibition = 14 % Inhibition = 14 % Inhibition = 17 % Inhibition = 19 oykAx o ^ hkA. THE" y X ' oj © £ f '° % Inhibition = 16 % Inhibition = 35 % Inhibition = 25 % Inhibition = 13

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Section E: Examples L- 613 to L- 628

Aw ΟγΑΑ 0 ✓O 'NH, tfpb OylkA % Inhibition = 13 % Inhibition = 16 % Inhibition = 15 % Inhibition = 51 F THE % Inhibition = 37 % Inhibition = 35 % Inhibition = 16 % Inhibition = 28 Anh Ah qp O 'NH, οΎ nr Cl <? ^NH; % Inhibition = 21 % Inhibition = 16 % Inhibition = 17 % Inhibition = 18 Oy * UA ο ά: Δ Jo ’ NH, THE ίΑ % Inhibition = 14 % Inhibition = 16 % Inhibition = 12 % Inhibition = 13

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Section F: Examples L- 629 to L- 636

Ah T % Inhibition = 27 % Inhibition = 15 % Inhibition = 10 % Inhibition = 13 0 ^ Ah O Ah Cr ’^ Br % Inhibition = 13 % Inhibition = 14 % Inhibition = 29 % Inhibition = 13

[000441] The present invention should not be limited in scope by aspects that are intended as illustrations of simple aspects of the invention, and any sequences of clones, DNA or amino acid that are functionally equivalent are included in the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the technique of the above description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[000442] The description of the United States Interim Order Serial Number 60 / 449,588, filed on February 26, 2003, and United States Interim Order Serial Number 60 / 540,229, filed on January 29, 2004, are hereby incorporated by reference, in their entirety.

[000443] All references cited herein are hereby incorporated by reference in their entirety.

Claims (4)

1. Compound, characterized by the fact that it presents formula 4 R ¹ nh ₂ where: R ¹ is C6-12 aryl or 5- to 12-membered heteroaryl; and each hydrogen in R ¹ is optionally substituted by one or more groups of R3; R3 is halogen, C1-12 alkyl, 3- to 12-membered heteroalicyclic, O (CR ⁶ R7) nR ⁴ , - (CR ⁶ R7) nC (O) OR ⁴ , or -C (O) NR ⁴ R ⁵ ; each R ⁴ and R ⁵ is independently hydrogen, halogen, C1-12 alkyl, 3 to 12 membered heteroalicyclic; each R ⁶ and R7 is hydrogen; each R9 and R ¹⁰ is independently hydrogen, or C1-12 alkyl; A ² is C6-12 aryl or 5- to 12-membered heteroaryl, and A ² is optionally substituted by one or more groups of R ³ ; and n is 0, 1,2, 3 or 4; or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt according to claim 1, characterized in that A ² is phenyl optionally substituted by one or more halogen. A compound according to claim 1 or 2, characterized in that R ¹ is a thiophene, pyrrole, thiazole, imidazole, pyrazole, pyridine or phenyl, and each R ¹ is optionally substituted by a group Petition 870190089642, of 10/09/2019, p. 476/482 2/2 R ³ , or a pharmaceutically acceptable salt thereof. 4. Use of a therapeutically acceptable amount of a compound, as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of a pharmaceutical composition to treat abnormal cell growth in a mammal, where the abnormal cell growth is cancer.